CZ294794A3 - Derivative of glutamic acid, process of its preparation and pharmaceutical composition containing thereof - Google Patents

Abstract

The present invention provides novel compounds that affect excitatory amino acid receptors and are useful in the treatment of neurological disorders. This invention also provides synthetic methods for the preparation of the novel compounds.

Description

A glutamyric acid derivative, a process for its preparation A composition which comprises it or a mixture thereof.

SUMMARY OF THE INVENTION The present invention relates to antagonists of an excitatory amino acid recipe for defective condition of an egg cell

In the mammalian central lier system (CHS), nerve impulse transfer is controlled. the interaction between the neurotransmitters released by neuronal transmission and the neuron receiving surface receptor. This leads to excitation of the Receiving Neuron. L-Glutamate, which is the most common neurotransmitter in the central nervous system, mediates the major extitator pathway in mammals and is related to excitatory amino acid (EAA) - Receptors that respond to glutamate. are called excitatory amino acid receptors (EAA recipes) (Wat. ~ kins and Evans, Arirn Rev. Phar macol - Toxicol, 21, p. 165 (198 l); Mahogany, Brodges and Cotman, Ann-Rev. Pharmacol. Toxicol -.29, p 365 (1989); Watkins, Krogssaard-Larsen and Honore, Trans-Pharm. Sci., 11, p.25 (1990)). Excitator amino acids are of great physiological significance, they play a role in numerous physiological processes, such as long-term potency (learning and memory), development of synaptic plasticity, movement control, breathing, cardiovascular control, and emotional perception.

Excitatory amino acid receivers are divided into two general types - Receptors, Directly coupling to cation channel openings in the cell membrane of neurons, are termed 1onotropicThese type of receptors are further subdivided into at least three subtypes, which are defined by depolarization by selective N-methyl agonists (NM 0 A), σ - omino - 3 - hydroxy - 5 - methyl isoxaz <11 - 4 ProPionic acid (AMPA) and kainic acid (KA). The second general type of recipe is G-protein or mediate-bound (metabotropic) excitatory amino acid receptor-This second type of

is coupled to numerous second mediator systems. resulting in the promotion of phosphoinositide hydrolysis, activation of phospolipase D, increased or decreased cAMP formation, and a shift in ion channel function of CSehoepp and Conn. Trends in Ptiarmacol. Sci., 14, p. 13 (1939)). Both types of receptors appear not only as mediators of normal synaptic transmission along the excitatory path, but also participate in the modification of synaptic junctions during the development and life of CSchoepp, Bockaert and Sladecsek, Trends in Fharmacol. 5ci. 11, SOS (1990); McDonald and Johnson, Brain Research Revievs, 15: 41 (1990)).

Excessive or inadequate stimulation of excitatory amino acid receptors results in neuronal cell damage or loss of the pathway of a mechanism known as exclusion toxicity. This process is considered to mediate neuronal degradation in various states. Medicine is trying to combat such degeneration of neurons, and addressing these degenerative neurological processes is an important therapeutic challenge.

Metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that bind to numerous secondary mediator pathways. This receptor function modulates presynaptic glutamate release and postsynaptic sensitivity of neuronal cells to glutamate excitation. Agonists of these receptors are useful for the treatment of acute and chronic neurodegenerative conditions and as antipsychotic. antispasmodic, analgesic, anxiolytic, antidepressant and antiemetic agents.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides excitatory amino acid receptors affecting a compound of formula I co ₂ r ⁴ (CH 2 Zn)

<I) h ₂ n co ₂ R ^p

k d 1? means OF NR5, oxygen or sulfur W -CH (3-p), - (CH ₂ ) _q -, - (CH ₂ ) q CH _{(3- p} ), - (CK ₂ ) qCO-, - (CH ₂ ) _q O-, - (CH ₂₎ ) _q CH = CH (CH ₂ ) _q -, - (CH ₂ ) _q CH = CH-, -CH = CHCO-, -CH = CHCOOR 6, - (CH ₂ ) _q CHOHR 6, - (CH ₂ ) _q CHOH, - <CH ₂ ) _q CO ₂ R 6, -O (CH ₂ ) _q -, NR 5, SO, SO ₂ oxygen atom or sulfur atom, n 0 or 1 m 0 or 1 P 0, 1, 2 or 3 q 0 to 6 r 1 or 2 3 0 or 1 provided that the sum of n, m, p and s is at least 1, R1 < and R2 is independently an aryl, substituted aryl- a heterocyclic group or a substituted heterocyclic group; R3 a hydrogen atom or a carboxyl protecting group, R4 a hydrogen atom or a carboxyl protecting group,

^£ R is hydrogen, alkyl having 1 to 10 carbon atoms, acyl or S0 ₂ (alkyl) groups having from 1 to 4 carbon atoms forming,

R ⁶ is alkyl having 1 to 10 carbon atoms, provided that when o is 1 Oas, zanemriá R ¹ radical from the group consisting tetrazolvlovou group, triazolyl, pyridinyl idaziriy nominal, pyrimidinyl, pteridinyl, 1,2,4- triazirt-0,5-dionyl. pyrazolonyl, 7H-purinyl, xanthinyl, 3-ethyl-5-hydroxy-1,2,4-triazolyl, 3-hydroxy, 1,2,4-thiadiazolyl, rhodium, hydantoins 1 o nu ap seudothi ohyd ant oiny io acid, and with the further proviso that when n is 1, m is 1 and W is NR ^£, S0, S0 _2, oxygen atom or sulfur atom, s = 1, and that in the case where n is 0 and z is 0, m is 1 and W is a group of formula

- (CH ₂ ) _q CO-, _ (CH ₂ ) _q O-, -CH-CHCO-, -CH-CHCOOR 6, - (CH ₂ ) _q CHOHR 6,

-CCH ₂₎ qCHOH. -CCHajqCOR ⁶ . -OCCH 3 -, NR ⁵ , SO, SO 2, or an oxygen atom, or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions comprising, as active ingredient, a compound of the formula I together with one or more substances selected from the group consisting of carriers, diluents and excipients.

The invention also relates to a process for the preparation of compounds of formula II

(II) where it represents an oxygen or sulfur atom,

In the -CH <3-p> group. - (CH2) qCHt3-p '. - <CH 2) q CO-,

- (CH 2) q O-, -CCH 2) q CH = CH 2 Cl 2 -. (CH 2) q CH = CH 2 -, -CH-CHCO-, -CHCHCOR ⁶ , -CCl ² , qCHQHR ⁶ , - (CH 2) _q CHOH, -CCH ³ JCOR ⁶ , -OCCH 2> q-, NR ⁵ . SO. SO2 oxygen or SJ / m 0 or 1,

P 0,1,2 or 3, q 0 to &

r 1 or 2 with 0 or 1,

R ¹ and R ² are independently aryl, substituted aryl group, a heterocyclic group or substituted heterocyclic group,

R ⁷ is hydrogen or a carboxyl protecting group, provided that when m is 1 and V is NR ⁵ , SO, SO 2 or oxygen, s is 1.

which according to the invention consists in that:

a) reacting a compound of formula IV

HIM.

- (CH2) _r

CO ₂ R ^e

CIV>

wherein R ³ represents a carboxyl group protecting group ar 1 or 2. with a coupling agent and a compound of the general formula

HZ'R * Vm <R ² > p wherein Z, R ¹ , V, R ² and m are as defined above, to obtain a derivative at the 3-position of the substituted pyroglutamate and

2) hydrolyzing the 3-position substituted pyroglutamate derivative.

The invention also relates to a process for the preparation of compounds of formula III

CO ₂ H

(III h ₂ n co ₂ r ¹⁰ wherein the group is -CH 3 -P → -CCH 2) q-, -CCH 2) q CH 3 -P, -CCH 2) q CO-,

-CCH2) qO-, - (Target2) qCH = CH (CH2) q-. -CCH 2) qCH = CH-,

-CH = CHCO-, -CH = CHCOR ^6th - <CH ² CH ² CHOH ⁶ . - (CH 2) q CHOH,

-C ⁶ H ⁶ COR ⁶ . -O (Cl 2) q -, NR ⁵ , SO. SO2 oxygen or 5 / y atom 0 or 1,

0. 1,2 or 3, up to 6 1 or 2

R ^{6 is an} aryl group, a substituted aryl group, a heterocyclic group or a substituted heterocyclic group.

R ^{9 is} tetrazolyl, triazolyl. pyridazinvlová. pyrimidinyl. pteridinyl. 1,2,4-triazine-3,5-dionyl, pyrazolonyl. 7H-purines, xanthinyl. S-ethyl-S-hydroxy-1,4-thiadiazolyl, 3-hydroxy-1,2,4-thiadiazolyl. rhodaninyl, hydantoinyl and pseudothiohydantoinyl.

R @ ¹⁰ is a hydrogen atom or a carboxyl protecting group which according to the invention consists in reacting a compound of the formula IV

wherein the R ⁹ carboxy group protecting group is ar 1 or 2 with a coupling agent and a compound of the general formula

HR ^ VmCR ^2> _P V wherein R ^2, R ⁹ have the above UAP above-nan, to obtain the derivative of the 3-substituted pyroglutanátu and 2) the derivative of the 3-substituted pyrog1utamátu hydrolysis.

The invention also relates to a process for the preparation of compounds of formula IV

Civ) where it means

R @ 1 is hydrogen or a carboxyl protecting group, R @ 1 or R @ 2, which according to the invention is characterized in that:

1) cyclopentadiene or cyclohexadiene is cycloaddated with a nitrosyl compound of the formula

ONCOOR ¹¹

- wherein R ^{11 is} benzyl or substituted benzyl to give a compound of formula V

where R ¹¹ and r are as defined above,

2) the obtained compound of formula (V) is oxidized to give a compound of formula (VI)

where R ¹¹ and r are as defined above,

3) carboxyl groups in a compound of formula VI are protected to give a compound of formula VII r ¹³ o ₂ c

CO ₂ R ^{: 2}

CVII) co ₂ r- ³ wherein R ¹¹ are as defined above and where is

R12 _and R13 carboxy-protecting groups a

4) removing the protecting group from the nitrogen atom of a compound of formula VII relates to the infiltration of one or more receptor-excitatory amino acids as well as to a method for detecting non-logical disorders that are affected by excitatory amino acid receptors by administering a compound of formula Examples of neurological disorders that can be treated with a compound of Formula I include brain deficiencies following cardiac bypass surgery, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huritington's chorea, amyotropic lateral sclerosis, demerition induced AIDS, muscle spasm, migraine headaches, urinary irregularities, psychosis, convulsions, perinatal hypoxia, cardiac arrest, hypoylycemic neuronal damage, npiate tolerance / withdrawal, eye and retinopathy diseases, perception disorders, idiopathic and drug induced Par'kinsori's disease. Anxiety, vomiting, brain swelling, chronic pain, and discinesia- The compounds of Formula I are also useful as analgesic and anti-depression agents.

The term "C 1 -C 10 alkyl" refers to a straight, branched or cyclic C 1 -C 10 alkyl hydrocarbon group, such as methyl, ethyl, n-propyl, i-propyl, ri, or methyl. an aryl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, n-octyl and decyl group. The term alkyl of 1 to 10 carbon atoms also includes alkyl of 1 to 6 carbon atoms and alkyl of 1 to A carbon atoms. Typical alkyl groups having 1 to 10 carbon atoms are, for example cyk1opropylová group, cyclobutyl, cykloPeritylová, cyclohexane] cyclohexyl and cycloheptyl ⁱⁿ g group- Typical alkyl groups having 1 to 6 carbon rucksack and ~ are, for example methyl, ethyl, n Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-Perityl, iso-pentyl and r-hexyl.

As used herein, the term "acyl" refers to a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms attached to a carbonyl group. Typical acyl groups are exemplified by formyl, acetyl, propionyl, butyryl, valeryl or caprylic groups.

By the term protecting group! carboxy is to be understood as meaning the group of one of the carboxylic acid ester derivatives which is introduced during the preparation for protecting or blocking the carboxyl group in the reaction of other functional groups. Such protecting groups are generally described in numerous known publications, such as Protecting Groups. in Organie Chemist, Chapter 3 (McOmie Ed, Plenum Press, 1973) and Green, Protecting Groups i.ri Organic Synthesis, 2 editions, Johm Wiley & Sons, NY, 1991. Examples of carboxy protecting groups include C 1 -C 6 alkyl, C 1 -C 3 arylalkyl, silyl, and alkenyl groups such as methyl, ethyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxy benzyl, 24,6-trimethoxybenzyl, 2,4,6-trimethoxybervzyl, benzhydryl, tert-butyl, tert-amyl, triethyl, trimethylsilyl, 1.1; - - - (1-methyl-1-methyl-1-en-3-yl) -prop-1-en-3-yl

As used herein, the term "amino-protecting group" means, as is generally the case in organic chemistry, a group which prevents an amino group from participating in the reactions of other functional groups in a molecule which, however, can be removed from the amino group again if desired Such protecting groups are described in Green and Wuts, ProtectinSe Groups in Organie Synthosis, 2nd Edition, Johm Wiley et Sons, New York, 1991, and Protecting Groups in Organie Chemistry. chemistry), Chapter 2 (JFW McOmie Ed, Pletium Press, 1973). As examples of such protective agents

groups are featured! benzyl, tert-butyl, tert-butyldimethylsilyl, triphenylsilyl, furyl, triyl, violetimido, trichloroacetyl, chloroacetyl, bonzyloxycarbonyl, methoxycarbonyl, 2-methylbenzyloxycarbonyl onylová,

2,2,2 -1 "ri ch 1 or e. X _y t he carb ony1ovά term aryl 'are always oriented aromatic group such as phenyl, and polynuclear aromatic groups such as naphthyl group such as 1-naphthyl or 2naftyiová) fluorenyl, for example 2-fluorenyl, anthracyl and feriarithryl · Substituted aryl "refers to an aryl group substituted with one or more moieties selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1 -C 6 alkyl, alkyl C 7 -C 10 -cycloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, carboxy, acetyl, formyl. carboxymethyl, hydroxymethyl, amino, aminomethyl, trifluoromethyl, or the aryl group is disubstituted on two adjacent carbon atoms with a C3-C10 alkylene, C2-C10 alkyleneoxy, C1-C10 alkylenedioxy group, a C 5 -C 6 cycloalkylerium group or a C 5 -C 6 cycloalkyleneoxy group, or a ring which, together with the two carbon atoms of the aryl ring to which it is attached, forms a ring. By way of example, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4 (isopropyl) phenyl, 4-cyclopentylphenyl, 4- (1,1,4,4-tetramethylbutyl) phenyl, 4-methylphenyl, 4-isopropylphenyl, -acetylphenyl, 4-trifluoromethylphenyl, 4-chlorferiyl, 3,4-dlchlorophenyl, 2-bromophenyl, 3-iodophenyl, 6-bromonaphthyl, 3,4-methylenedioxyphenyl, indan-5-yl, 1,2,3,4-tetrahydronaphthalene t-5-yl and 1,1,4,4-tet thy frames}. -1,2,3,4-tetahydronaphth-5-yl The term substituted phenyl is herein in each case a mini-phenyl group substituted by one or more of halogen, cyano, nitro, alkyl of 1 to θ carbon atoms. , C1-C4alkoxy, carboxy, acetyl, formyl, carboxymethyl and hydroxymethyl, amino, aminomethyl or trifluoromethyl

As used herein, a heterocyclic group refers to a five-membered or six-membered group containing carbon atoms and one to four heteroatoms selected from nitrogen, oxygen or sulfur, optionally condensed with a second five-membered or six-membered group containing atoms These five- or six-membered rings may be saturated or unsaturated. Examples of heterocyclic groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl._and thlazolyl, thiazolidiriyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, rxadiazolyl, tetrazolyl, thlatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiaziazylyl, oxazlnyl, triazines, thiadiaziriyl, oxadiazinyl, dithiazinyl, dioxazirtyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriaziriyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidylⁱⁿβ, pyrrolldinyl, piperidinyl, piperazirinyl, pyrazolidinyl, pyrimidinyl, imidazolidinyl, morpholinyl, pyranyl, furanyl, thiomorpholinyl, 1,2,4-triaziri-3,5-dionyl, pyrazolonyl, pteridylinyl, rantanothiinyl, rhanthinyl, rantanilinyl, rantanothiinyl, rantanilinyl, rhanthinyl, The term substituted heterocyclic group refers to a heterocyclic group substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, riitro, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms. 6 carbon atoms, carboxy, C 1 -C 4 alkoxycarbonyl, hydroxymethyl, amino, and and a trifluoromethyl group. In addition, the heterocyclic group may be fused with one or two aryl groups to form benzo-fused groups such as, for example, benzoxazolyl, benzisooxazolyl, benzofuranyl, benzothiazolyl, thianaphthenyl. benzothiazolyl, benzimidazolyl, indolyl, dibenzofuranyl and dibenzothiophenyl groups. Examples of substituted heterocyclic groups include 1,2,3,5-tetrahydrodibenzofuranyl. 2-methylbenzofuranyl and 3,5-dimethylisoxazolyl.

In order to clarify the meaning of the group of the formula ZnCR ¹ > sV _m CR 2 j _P where Z is an oxygen atom and n is 1, the following groups are given -

O o

Γ \ /)

O

The invention is also a bast; compounds wherein Z is sulfur or NR5.

The term "affecting" here always attenuates the action of a compound of formula I as agonists or partial agonists or antagonists on one or more excititor amino acid receptors. The term recePtor excitatory amino acid refers to iontopic glulmatic recePtors, receptors that directly coupled through the ion channel apertures in the neuronal cell membrane and to metabotropic glutamate receptors, receptors that coupled ria cellular e.fectors via GTP binding proteins. acid "refers to the β-isotropic glutamate receptor, which is selectively activated by N-methyl-D-aspartate (NMDA),

A pronounced neurological disorder means acute as well as chronic neurodegenerativity conditions, including brain insufficiency After surgical cardiac bypass, stroke, cerebral ischemia, colonic trauma, head trauma, Alzheimer's disease, Huntlngt's chorea, amyotropic lateral. sera lerosa, AIDS-induced dementia, pineal hypoxia, cardiac arrest, hypoglycemic neurorial damage, eye problems and retinopathy, perception disorders, idiopathic and drug-induced Parkinson's disease. The term also includes other neurological conditions that are caused by glutamate dysfunction, including muscle spasm, migraine headaches, urinary incontinence, psychosis, brain edema, chronic pain, convulsions and delayed discinesia

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (I) - These salts may exist in association with acidic and basic groups of the molecule, which may be acid addition salts, Primary, Secondary, Tertiary, or Quaternary. ammonium salts, alkali metal or alkaline earth metal salts. Generally, an acid addition salt is prepared by reacting a compound of Formula I with acids. Alkali metal and alkaline earth metal salts are prepared by reacting the hydroxide form of the desired cation with a compound of formula I wherein R 3 and / or R 4 is hydrogen. 17 The acids commonly used to prepare such salts include inorganic acids such as e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids as well as organic acids such as, for example, para-toluenesulphoric, methanesulfonic, oxalic, para-bromophenylisulfonic, carboxylic, succinic, citric, benzoic and acetic acids and related, inorganic acids Examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogensulfate, sulfite, hydrogensulfite, phosphate, ammonium salts, monohydrogen phosphate, dihydrogen phosphate, metaphosphate., Pyrophosphate, chloride, bromide, iodide, acetate, propionate, docanoate, caprylate, acrylate format, i sobutyrate, caprate, heptanoate, propiolate, oxalate, malorate, succinate, suberate, sebacate, fumarate, hippurate, maleate, butin-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulphonate, xylene sulphonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, σ-hydroxybutyrate. glycolate, maleate, tartrate, methanesulphonate, proparisulphonate, raffen-1-sulphonate, naphthyl- 2-sulphonate, mandelate, magnesium, tetramethylammonium, potassium, trimethylammonium, sodium, methylammonium and calcium saltsA particular group of compounds of formula I are those wherein:

Z is an oxygen or sulfur atom,

W - (CH _{2) q} CH = CH-, - (CH _{2) q} -, - <CH ₂₎ q O-,

- (CH ₂ ) q CH-CH (CH 2) q -, -O (CH ₂ ) q 'a

i) n 0, s 1, m 0, ρ 0 and R 1 is a tetrazole group in the 3 or triazolyl group; ii.) ni, s 1, m 0, p 0 and R ^{1 is} a phenyl or naphthyl group which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, (C 1 -C 6) alkyl, (C 7 -C 10) alkyl, (C 3 -C 6) cycloalkyl, alkoxy C 1-4 alkyl, carboxy, acetyl, formyl, carboxymethyl, hydroxymethyl amino, aminomethyl and trifluoromethyl, or disubstituted on two adjacent carbon atoms with C 3 -C 10 alkylthio; (C 2 -C 10) alkyl, (C 1 -C 10) alkylenedioxy, (C 5 -C 6) cycloalkylene or C 5 -C 6 -alkyloxy group, or together the carbon atom arylové.ho nucleus to which they are attached form a ring or PyrimJ.dylo-;

or a 1-methyl tetrazin-5-yl group;

(Iii) n 1, s 1, m 0 or 1, P 1 or 2 and R ¹ is phenyl;

or triazolyl and each R ² and independently of each other is a pyridyl or phenyl group which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy or cyano; nitro, C 1 -C 6 alkyl, C 7 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, carboxy, acetyl, formyl, carboxymethyl, hydroxymethyl, amino, an aminomethyl group and a trifluoromethyl group; and

P 0 to 6 r 1 a

R ³ and R ^{4 are} each hydrogen- ·

2v]. an important group are the compounds of formula (I), wherein

2. an oxygen or sulfur atom;

W is -CH = CH-, - (CH ₂ ) CH = CH-. - (CH ₂ ) ₃ -, - (CH 2) 2 -,

- (CH 2) O - or an oxygen atom - or - (CH 2) 0 - a

i) n 0, s 1, m 0, p 0 and R 1 is a tetrazol-1-yl, tetrazol-2-yl or 1,2,4-triazolyl group _; (ii) ni, with 1, m 0, p 0 and R ¹ phenyl, 2-methylphenyl;

acid, 4-methylphenyl eriy salicylic, 4-f met.hoxy enyl, 4-isoPropylfeny1 ovcjli 4 - ί * ^- * · / J op the 1 1 o ou »4 - (1, 1, 4,4-t etramethyIbut y 1 ) - 1-phenyl, 4-acetylphenyl, 4-trifluoromethylphenyl, 4-

chlorophenyl, 2-bromophenyl, 3-iodophenyl, 1-naphthyl;

2-riaphthyl, 6-bromonaphth-2-yl, 1,5-bromonaphth-2-yl, 3,4-methyleridioxyphenyl, indan-5-yl, 1,2,3,4-tetrahydrofuran ethyl, 1,1,4,4-tetramethyl-1,2,3,4-tetramhydroraphthyl, fluoren-2-yl, dibenzofuran-2-yl, 5,6,78-1 tetramethyl 2-methylbenzofuran-2-yl, 2-methylbenzofuran-5-yl, bertzothiophon-5-yl, pyrimidin-2-yl or 1-methylbenzoyl-5-yl v _t ; iu oi <u ρ 1 nu ^! iii) n is 1, s is 1, m is 0 or 1, ρ 1 or 2 and R d is phenyl or 1,2,4-trlazolylovou and each R ² independently denotes a 2-pyridyl or phenyl, 2-chlorfonylovou, 4-chlorophenyl and 4-trifluoromethyl, r 1 and r

R ³ and R ⁴ are hydrogen, £.

Although all compounds of formula I of the invention have an effect on metabotropic non-amino acid and NMOA excitatory amino acid receptors, certain compounds of Formula 1 of the invention are preferred for use. Preferably Z is O or S, η 1, with 1, R1aryl a group substituted or substituted, a heter ocyclic group substituted or substituted, m 0 or 1, W by the formula ~ (CH ₂ ) _q O-, - (CH ₂ ) _q CH = CH-, - (CH ₂ ) q CH = CH ( CH ₂ ) q -, - (CH ₂ ) _q - or

-O (CH ₂ ) _q q 0 to 6, or 1 and R ² an unsubstituted or substituted aryl group, a heterocyclic group substituted or substituted Certain compounds of formula (I) of the invention are particularly advantageous in view of their effect on metabotropic receptors excitatory amino acids and NMOA receptors for excitatory amino acids. Z represents an oxygen atom, R1, P ¹ riesubstituovanou aryl or substituted phenol R ² is unsubstituted or substituted, and R ³ and R ⁴ is hydrogen knows y. As representative, the compounds of this more preferred group of compounds of formula (I) of the present invention are:

3- (4-phenylphenoxy) glutamic acid,

3- (3-Phenylphenoxy) glutamic acid

3- (4-Benzyloxy-phenoxy) -glutamic acid.

3- (1,6-dibromo-2-naphthyloxy) glutamic acid,

- (1-naphthyloxy) gutamic acid,

3-C5-indanyloxy-glutamic acid.

3- (2-methyl-5-benzofuranyloxyigiutamic acid) a

3- (5-Benzothiophenyloxy) glutamic acid.

Certain compounds of formula I of the invention are particularly preferred with respect to the effect on metabotropic excitatory amino acid receptors and NMDA excitatory amino acid receptors. The most preferred compounds of formula I according to the invention are selected from the group consisting of:

3- <4-methylphenoxyglutamic acid,

3- (4- (6-phenylhexyl) phenoxy) glutamic acid,

3- <4- (3-phenylprop-2-enyl) phenoxy] glutamic acid,

3- (6-bromo-2-naphthyloxy) -glutamic acid,

3- (4- <2- (4-nitrophenyl) ethenyl) phenoxy) glutamic acid,

3- (2-fluorenoxy) glutamic acid,

3- (2-dibenzofuranoxy) glutamic acid a

3- (5,6,7,3-tetrahydro-2-dibenzofuranoxy) glutamic acid.

The compounds of the formula I according to the invention have at least two asymmetric carbon atoms

(R ²⁾ p

Asymmetric centers are a carbon atom having an NH2 group (2 >) and a carbon atom having a group of the general formula

ZNCR ^1> SV _m (R 2 j _P (4 or 5). As such, the compounds of the formula I as diastereomers, enantiomers or raceraických modification (e.g. racemate). The invention includes all enantiomers and diastereomers, mixtures of enantiomers (including racemates When the symbol r is 1, the configuration of the preferred diastereomers is 2S, 4R and 2S, 4S, and when the symbol r is 2, the configuration of the preferred diastereomers is 2S, 5R, and 2S, SS. 4SR for compounds where r is 1. Preferred racemates are 2SR.SRS and 2SR.5SR for compounds wherein r is 2- The most preferred stereoisomer configuration is 2S.4S or 2SSS as shown:

CC ⁴ R ⁴

The compounds of formula I according to the invention are prepared from compounds of formula IV. The preparation of compounds of formula IV wherein r is 1. is described in the literature (Ohta, Kosoi and Nozoe, Tetr. Lett., 29, p. 329, 1988, and Yong Kyun Lee and Takeo Kaneko-, Duli. Chem. Soc. Jap., 1973, vol. 46, no. 11, pp. 3494-34. An improved process for the preparation of compounds of formula IV as intermediates from cyclopentadiene or from cyclohexadiene is described in Scheme I.

Scheme I

In general, compounds of formula V are prepared by cycloaddition of cyclopenadiene or cyclohexadiene to the nibroso compound of formula ONCOOR ¹¹ . The cycloaddic is oxidized to give the dicarboxylic acid, a compound of formula VI. The free carboxylic acid groups are protected to give the fully protected intermediate of formula (VII). The protecting groups are then removed from the nitrogen atom under suitable conditions for cyclization to the compound of formula IV.

The invention relates to an improved process for the preparation of an intermediate of formula (IV). The compound of formula (V) is prepared by reacting cycllepenbadiene or cyclohexadiene with a dienophile, with a rtibrosoformab esber. Nibrosoformab is prepared in sibu by oxidation of N-hydroxycarbamab. N-Hydroxycarbamab is prepared in a manner similar to that described by Helu. Chim.-Acba, 70, p. 554 (C1987). The reaction is preferably carried out by adding a slurry or solution of the oxidizing agent to a cold solution containing N-hydroxycarbamate and a dieride. oxidizing agents for the preparation of dieriophile are, for example, tetrabutylammonium iodate, sodium iodide. and the potassium iodoate. A preferred oxidizing agent for this reaction is tetrabutylammonium iodate. Suitable solvents for this reaction are organic solvents such as methylene chloride or chloroform. The reaction is generally carried out at a temperature of about. -20 to about 0 ° C, preferably at -5 ° C. The reaction is quenched by carefully adding a 10½ aqueous sodium hydrogen sulfate solution. The compound of formula V is usually purified by flash chromatography on silica gel. The compound of formula V is oxidized to prepare a dicarboxylic acid intermediate of formula VI. Suitable oxidizing agents for this reaction include ozone, osmium tetrachloride / sodium periodate and potassium permanganate. The preferred oxidizing agent for this reaction is potassium permanganate. The oxidation is generally carried out in a biphasic mixture comprising an organic phase comprising a compound of formula (V) and an inorganic phase containing potassium permanganate. To facilitate oxidation, transfer of the oxidizing agent to the organic phase, a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate may be added. The reaction is generally carried out in an ice bath to maintain the temperature of the reaction mixture at about 15 ° C to about 30 ° C, preferably at about 18 ° C. about 27 ° C. Suitable solvents for the organic phase are organic solvents, for example toluene, xylene and benzene. The oxidation is generally complete after approx. The reaction product, after separation of the phases and removal of the inorganic fraction by extraction, is used in the next reaction step without further purification. The free carboxylic acid group of formula (VI) is protected to yield a compound of formula (VII). Methods for protecting carboxyl groups are generally described in the publication. Including GrouPS in Organic Chemistry, Chapter 3 (McOmj.e Ed-, Plenum Press, 1973) and Grecn Wuts, Protectirig GrouPs in Organic Synthesis, 2 editions, Johm Wiley & Sons, NY, 1991. Ester protecting groups are preferred for the preparation of compounds of formula (V). Carboxylic acid groups can be protected as alkyl esters of 1 to 5. C 6 -C 6 alkylsubstituted, substituted C 1 -C 6 alkyl esters or aryl esters. A preferred ester group is an alkyl ester having 1 to 8 carbon atoms in the alkyl moiety, the most preferred methyl ester group being prepared by reacting the intermediate of formula VI with trimethyloxonium tetrafluoroborate in the presence of an amine base. N, N-diisopropylethylamine, N-methylmorpholine and Pyridine. The preferred amine base for the reaction is Ν, N-diisopropylethylamine. temperature below 33 ° C. The compound of formula (VII) is purified by flash chromatography on silica gel. The nitrogen protecting group of the compound of formula (VII) is removed under conditions suitable for intramolecular cyclization to give a compound of formula (IV). Suitable catalysts Palladium on carbon, platinum on carbon, palladium on alumina, platinum oxide, rhodium on alumina or rhidum rta carbon are mentioned for the nitrogen deprotection reaction. A preferred catalyst for this reaction is 10X palladium on carbon. Suitable solvents for this reaction are polar organic solvents such as tetrahydrofuran, ethyl acetate, methanol and ethanol. A preferred solvent for this reaction is tetrahydrofuran. The reduction is carried out under a hydrogen pressure of 310-414 kPa. and at a temperature of about 20 to about 40 ° C, preferably at room temperature. The catalyst may be removed by filtration and the compound of formula IV may be purified by flash chromatography of silica gel and / or recrystallization.

The compounds of the invention are chemically prepared from the intermediate of formula (IV) by a number of different routes. The specific processes described herein may be combined with other methods for preparing compounds of Formula I. The following description of the preparation is therefore not intended to be limiting and merely illustrates the process. Scheme II illustrates a process for the preparation of compounds of formula I wherein Z is O or S and n is 1.

Scheme II

co ₂ h

A, i ^r, > k (ch ₂ ), τ w, m

(R

V / ^{(R2) &} gt ;.

w /

H ₂ N CO ₂ R ⁷

II

Generally, a compound of formula IV is reacted with a coupling reagent and a compound of formula

HZ CR ^{1 is} VCRCR ² ) _P wherein the individual symbols are as defined above and Z represents a sulfur atom or an oxygen atom, to yield at the 3-position a substituted pyroglutamate derivative. compounds of formula VIII. This intermediate is hydrolyzed to give a compound of formula II. The carboxylic acid groups of the compound of formula (II) may optionally be midified. or converted to a pharmaceutically acceptable salt for the preparation of compounds of Formula I.

According to this scheme, a compound of formula IV is reacted with a compound of formula HZ '(R 1) _with W _m (R 2) _p to give the 3-position of a substituted pyroglutamate derivative, a compound of formula VIIa, a preferred population reagent. . prepared by reacting a dialkylazinedicarboxylate with triphenyl phosphine (Mitsunobu, Synthesis, pp. 1-18 (1961)). A useful dialkyl azodicarboxylate For this reaction, diethyl azodicarboxylate is preferably a solution comprising a compound of formula IV, triphenylphosphine and a compound of formula

H 2 '(R 1) _with W _m (R 2) p in an organic solvent with diethyl azodicarboxylate solution- Suitable organic solvents Anhydrous aprotic solvents such as ether or tetrahydrofuran are mentioned for this reaction. The reaction is generally carried out at a temperature of about 0 to about 25 ° C. preferably initially at 5 ° C. The reaction is generally complete after about 18 hours.

The intermediate of formula VIII is then hydrolyzed to obtain a compound of formula II wherein R ⁷ represents a protecting group of carboxyl group represent hydrogen atoms or hydrolysis is generally carried out using an inorganic base, for example lithium or sodium hydroxide in a water / rich organic rozpouštědlo- suitable system for This reaction is a mixture of water and tetrahydrofuran. The hydrolysis is generally carried out at a temperature of about 25 ° C to about 65 ° C, preferably at room temperature. a temperature of about 60 to about 65 ° C.

Compounds of formula (I) wherein R ³ and R ⁶ are other than hydrogen are prepared from compounds of formula (II). These compounds are prepared by known methods of organic synthesis. For example, esters of the compounds of formula (I) are prepared as described in Protectirig Groups in Organic Chemistry, (MoOmie) and Oreen Wuts, Protectirig Groups in Organic Synthesis ™, *ηκονιι douč fir, m * £ Or'C t?

(n is zero, with 1 and R1 tetrazolyl, triazinyl, triazinyl, pyridazinyl, pyrimidinyl, Pteridinyl, 1,2,4-triazine-3,5-dlenyl, pyrazolonyl, 7H-purinyl, xanthinyl, 3-ethyl) 5-hydroxy-1,2,4-thiadiazolyl, 3-hydroxy-1,2,4-thiadiazolyl, rhodaninyl, hydantoinyl or pseudohydantoinyl, is illustrated in Scheme III.

Schéna III

III

W _n

'W' (R ²⁾ C

Generally, the compound of formula IV is coupled with a tetrazolyl or triazolyl compound to give the 3-position of the substituted pyroglutamate derivative, a compound of formula IX. This intermediate is hydrolyzed to give the carboxylic acid, a compound of formula III. This compound is optionally esterified or converted to a pharmaceutically acceptable salt prepared for the preparation of compounds of Formula I.

The compound of formula IV is reacted with a coupling agent and a compound of formula

HR VmCR ^ ² ^ wherein R ⁹ group selected from the group consisting of tetrazolyl group. triazolyl. pyrldazinyl. pyrimidinyl, pteridinyl, 1,2,4-triazine-3,5-dionyl. pyrazolonyl,

7H-purir. xanthinyl. 3-ethyl-5-hydroxy-1,2,4-thiadiazolyl, 3-hydroxy-1,2,4-thiadiazolyl, rhodaninyl, hydantoinyl or Pseudohydantoinyl and other symbols are as defined above to obtain at the 3-position substituted a pyroglutamate derivative, a compound of formula (IX). ační ^m

The reagent for this reaction is the Mitsunobo reagent, prepared by reacting a dialkylazodicarboxylate with triphenylphosphorium (Mitsuriobu, Synthesis, pp. 1-18 (1981)). Useful dialkyl azodicarboxylate For this reaction, diethyl azodicarboxylate is preferably a solution comprising a compound of formula IV, triphenylphosphine and a compound of formula

HR9W _m (R2) _p in an organic solvent with diethyl azodicarboxylate solution Suitable organic solvents Anhydrous aprotic solvents such as ether or tetrahydrofuran are mentioned for this reaction. The reaction is generally carried out at a temperature of about 0 to about 25 ° C, preferably initially at 5 ' C. The reaction is generally complete after about 18 hours.

The intermediate of formula (IX) is then added. hydrolyzed to obtain a compound of formula III where R ¹⁰ carboxyl protecting group, or represent hydrogen atoms hydrolysis is generally carried out using an inorganic base such as lithium hydroxide Riebe carbonate in water / organic solvent - suitable system for this reaction is a mixture of water and The hydrolysis is generally carried out at a temperature of about 25 ° C to about 65 ° C, preferably about 60 ° C to about 65 ° C.

Compounds of formula I wherein R ³ and R ⁴ are other than hydrogen are prepared from compounds of formula III. These compounds are prepared by methods known per se for organic synthesis. For example, esters of the compounds of formula (I) are prepared as described in Protecting Groups in Organic Chemistry (McOmie) and Sreen Wuts. A process for the preparation of compounds of formula (I) wherein:

Z is an oxygen atom, n zero, s zero is illustrated in Scheme IV.

Scheme IV

Generally, a compound of formula IV is reacted with an alkylating agent to give the 3-position of a substituted pyroglutamate derivative, a compound of formula X wherein Z is O, η 1, and a V group

-CH <3-p>. - _<CH2) q-, -CCHs) q <p 3>. -CCH 3 is CO-, -C (CH 3) q CH-CH-. -CH = CHCO-, -CHCHCOR ^6th -CCH2 íqCHOHR ^6th - <CH2> qCH0H or

- <CH ₂ jqCOR ⁶ .

This intermediate is hydrolyzed to give the carboxylic acid compounds of formula XI. This compound is optionally esterified or converted into a pharmaceutically acceptable salt prepared for the preparation of compounds of formula (I).

The compound of formula IV is reacted with a coupling agent and a compound of formula

XV'CR 2) _P wherein X represents a liberated group such as a halide, triflate, mesylate or tosylate and the other symbols have the meaning given above.

Preferably, the solution containing the compound of formula IV is treated with an alkylating agent solution. Suitable amine bases include, for example, triethylamine, Ν, N-diisopropylethylamine, N-methylmorpholine and Pyridine. A preferred amine base for this reaction is Ν, N-diisopropylethylamine. Suitable organic solvents for this reaction are, for example, methylene chloride; ether, tetrahydrofuran and acetonitrile. The reaction is preferably carried out at a temperature of about 0 to about 80 ° C. When triflate is used as the alkylating agent, the reaction is carried out at a temperature of about 0 to about 20 ° C. When a halide is used as the alkylating agent. The reaction is carried out at a temperature of about 25 to about 80 ° C.

The intermediate of formula (X) is then hydrolyzed to give a compound of formula (XI) wherein the R ¹¹ is hydrogen or a carboxy protecting group. The hydrolysis is generally performed using an inorganic base such as lithium or sodium hydroxide in a water / organic solvent system. This reaction is a mixture of water and tetrahydrofuran. The hydrolysis is generally carried out at a temperature of about 25 to about 65 ° C, preferably at a temperature of about 60 to about 65 ° C.

Compounds of formula (I) wherein R ³ and R ⁴ are other than hydrogen are prepared from compounds of formula (XI). These compounds are prepared by methods of organic synthesis known per se. For example, esters of compounds of formula (I) are prepared by Protecting Groups in Organic Chemistry, (McOmie) and Green Wuts, Protecting Groups iri Organic SynthesisThe method for preparing compounds of formula I wherein 2 is 1, n 1, is zero, is illustrated in Scheme V 31

Scheme V

In general, the compound of formula IV is reacted with an alkylsulfonyl chloride. with an alkylsulfonic anhydride or arylsulfonyl chloride to give the alkylsulfonate or arylsulfonate of formula XIX. This intermediate is then reacted with a compound of formula

H ² _n t (R ² ) p wherein Z is a sulfur atom and the other symbols are as defined above. This intermediate is hydrolyzed to give the carboxylic acid, a compound of formula XI. This compound is optionally esterified or converted to a pharmaceutically acceptable salt prepared for the preparation of compounds of formula (I).

The compound of formula IV is reacted with an alkylsulfonyl chloride, an alkylsulfonic anhydride, or an arylsulfonyl chloride in the presence of an amine base to give a compound of formula XIX wherein ^R11 is alkylsulfonic or arylsulfin such as toluenesulfonyl, methanesulfonyl or trifluoromethylsulfonyl. As examples of typical salkylsulfonyl chlorides, α122 anhydrides; The sulfonic acids or arylsulphoryl chlorides include p-toluenesulphonyl chloride, methanesulphonyl chloride and trifluoromethanesulphoric anhydride. Suitable amine bases for this reaction include, but are not limited to, triethylamine, N, N-diisopropylethylaripyridine and dimethyl aminopyrrolidine. The reaction is generally carried out with a dry organic solvent such as dry methyl chloride or tetrahydrofuran at a temperature of about -7 to 8 ° C. Approximately 0 “C. Preferably, the cold solution containing the compound of formula (IV) and the amine base in a dry organic solvent is treated with alkylsulfonyl chloride, alkylsulphonic anhydride or arylsulfonyl chloride.

The intermediate of formula XIX is then reacted with a compound of formula

H 2 _n W '(R 2) _P wherein the 2-sulfur atom and other symbols are as defined above. The reaction is carried out in the presence of an amine base, such as triethylamine, N, N-diisopropylethylamine, Pyridine and dimethylaminopyridine. Suitable solvents for this reaction include methylene chloride ether, tetrahydrofuran and acetone. "N 50" C. When R ^{14 is} trifluoromethylisulphenyl, the reaction is preferably carried out at a temperature of about -20 ° C to about 0 ° C.

The product of this reaction is then hydrolyzed to give a compound of formula XI, wherein R ¹¹ represents a hydrogen atom or a carboxyl group- prevent hydrolysis is generally carried out using an inorganic base, for example lithium or sodium hydroxide in a water / solvent rich organic. A suitable system for the reaction is a mixture of water and tetrahydrofuran. The hydrolysis is generally carried out at a temperature of about 25 to about 65 ° C, preferably at a temperature of about 60 to about 65 ° C.

Compounds of formula I wherein R ³ and R ⁴ are other groups than hydrogen are prepared from compounds of formula XI - These compounds are prepared by methods of organic synthesis known per se. For example, esters of compounds of general formula

v. ')' t. ·· (> ·

They are prepared as described in Protecting Groups in Drganic Chemistry, (McOmie) and Green Vuts. Protecting Groups in Organic Gynthesis.

Process for the preparation of compounds of formula I wherein Z represents a group NR ⁵ or, is outlined in Scheme VI.

Scheme VI

IV is oxidized to a compound of formula XII with an unsuitable reducing agent XIII. This intermediate was

In general, a compound of formula XII is used. This compound is reacted with an amine in the presence to obtain a compound of formula hydrolyzed to give a compound of formula XIV. The carboxylic acid groups of formula (XIV) may optionally be modified or converted to a pharmaceutically acceptable salt prepared for the preparation of compounds of formula (I).

According to the above scheme, a compound of formula IV is oxidized with a suitable oxidizing agent to give a 3-keto-pyroglutamate derivative of the compound of formula XII. The hydroxyl group is oxidized to the ketone by oxidizing agents and methods known in the art, such as Swern oxidant or other dimethylsulfoxide (OMSO) reagents (Mancuso, Huang, and Swcrn, J-Org, Chem. 43, pp. 2480-42). 2482 (1978), Epstein and Sweat, Chem Rev., 67, pp. 247-260 (1967), and Smi + h, Lecnay, Lin, Nelson and Bali, Tetr. Lett, 29, pp. 4.9-52. (1988) A preferred oxidizing agent for this purpose is a mixture of oxalyl chloride and dimethylsulfoxide, and in general, oxalyl chloride and dimethylsulfoxide are mixed in an organic solvent such as methylene chloride at a temperature of about -78 ° C to obtain the oxidizing agent. a solution of the intermediate alcohol, a compound of formula IV, is added to the cold oxidation reaction solution. This mixture is then treated with N, N-diisopropylethylamine and the resulting mixture is cooled to about -78 ° C to -15 ° C. is quenched by addition of saturated ammonium chloride solution.

A compound of formula XIII is prepared by reductive amination of an intermediate of formula XII- A compound of formula XII is reacted directly with a compound of formula

HZ (R 1) _with W _m (R 2) p wherein R 2 is NH or N-C 1 -C 10 alkyl and the other symbols are as defined above, in the presence of a suitable reducing agent. The preferred solvent for this reaction is anhydrous methanol. The reaction is generally carried out at room temperature. The intermediate of formula (XIII) is then reacted with sodium cyanoborohydride and sodium cyanoborohydride. hydrolyzed to a compound of formula XIV wherein R ¹² is hydrogen or SKU ^-

Pirium carboxyl protecting group The hydrolysis is generally carried out using an inorganic base such as lithium hydroxide or sodium hydroxide in a water / organic solvent system. A suitable system for this reaction is a mixture of water and tetrahydrofuran. The hydrolysis is generally carried out at a temperature of about 25 ° C to about 55 ° C, preferably about 60 ° C to about 65 ° C.

Compounds of formula (1) wherein R 3 and R ⁴ are other than hydrogen are prepared from compounds of formula (XIV) - These compounds are prepared by methods of organic synthesis known per se. For example, esters of the compounds of formula (I) are prepared by the method described in Protecting Groups in Organic Chemistry (Mc-Omle) and Green Wuts. Examples of prepared compounds that fall within the scope of the invention are listed in the whiteboard

Table Ϊ

Compounds of formula (I)

number 2 R.1 1 0 females 1 O C. with phenyl 3 0 4-Methylphenyl 4 0 2-methyl ferryl 5 0 4-Methoxyphenyl 6 0 4- (isopropyl) phenyl 7 0 4 - cy k 1 operations 1 pheny 1 8 0 4- (2,2,4,4-tetra) methylbutylphenyl 9 0 4 - and r; S tions 1. F en s 1 10 0 4 -1 r i f 1 uor me t h y 1 f er iy 1 1 1 0 3,4-dichlorophenyl 12 0 phenyl 13 0 feriyl 14 0 phenyl 1 5 0 phenyl

I _ W R n m Ρ - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - - 1 0 0 - 4-eryl 1 0 0 - 3-phenyl 1 0 0 4- _(CH2) f eriyl 1 1 1 2 ~ (CH ₂ ) phenyl 1 1 1

Γ Art I (continued) Number AND P 1 W R 16 0 f i 'ny 1. 4 - ((CH ₂ ) 6) phenyl 1 7 0 phenyl 4- (CH ₂ CHCH) phenyl Ί 6 0 phenyl 4- (CH = ^; CH) 4-nitrophenyl 19 Dec 0 phenyl 4- (0) phenyl 20 May 0 phenyl 4- (OCH ₂ ) phenyl 21 0 naphth-2-yl - - 22nd 0 6-Bromo-naphth ^- 2-yl- - - Ί No O 0 1,6-dibromonaphth-2-yl ' - - 24 with naphth-2-yl - - 25 0 1-naphth-1-yl - - 26 0 5,6,7,8-tetrahydro- - riaf t-1-yl - - 27 Mar: 0 5,5,8,8-tetramethyl-6 7-di ~ dihydronaphth-2-yl - - 28 0 Indan-5-yl - - 2.9 0 3,4-methylene- dio * yphenyl - - 30 0 fluoren-2-yl - - 31 0 dlbenzofuran ^- 2-yl ... - 3 2 0 5,6,7,8 — Letrahydro- dibenzofuran-2-yl • _ - 33 0 2-Methyl lbertzof uranium ^- 5- yl- - 34 at berizotbiophen-5-yl - - 35 0 phenyl 4-CH Pyridin-2-yl- 4-chloro phenyl 3 6 with 1,2,4-triazol-3-yl _4-CH2 phenyl 3 7 with 1,2,4-triazol-3-yl _1-CH2 phenyl 38 with 1,2,4-triazol-3-yl 5-CHCH2-chlorophenyl 39 with Pyrimidin-2-yl - - 40 with 1- (N-Methyl) - tetrazol-5-yl

- 1,2,4-triazol-3-yl;

1 1

1 1

1 1

1 1

1 1

Ο Ο

Ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ι η

I V V

1 2

Ί 1

1 1

1 1 ο ο ο

0 0 ί &

Table I (continued) Number Z R ¹ y R n n p 42 tetrazol-2-yl - - 0 0 0 43 tetrazol-1-yl - - 0 0 0 50 0 females 1 4-c <i2) females 1 1 1 1 51 0 females 1 4 - ((0111> 4) phenyl 1 1 1 S1oučenlna obecná of Formula I is being prepared stereosper; i f i oky

according to the scheme VIIScheme VII

! -Boc

XV

xvm

IIA

Generally, 4-hydroxy-L-proline is protected by a nitrogen atom, on a carboxyl group and on a hydroxy group. The fully protected compound is oxidized and partially deprotected to give a compound of formula XVII. The compound of formula (XVIIgg) is reacted with a coupling reagent and a compound of formula (I)

H 2 '(R 1) _with W _m (ft 2) _p wherein each symbol is as defined above and wherein Z' is O or S to give the 3S, 5S-3-substituted pyroglutamate, a compound of formula XVIII. This intermediate is hydrolyzed to give a compound of formula IIA. The carboxylic acid groups of formula (HA) may optionally be modified or converted to a pharmaceutically acceptable salt by a preparation of compounds of formula (I).

According to the scheme, 4-hydroxy-L-proline is converted to the methyl ester in a manner known per se. Suitable methods for preparing esters are described in Protecting GrouPs in Organic Chemistry, (McOmie) and Greeri Wuts. Protecting GrouPs in Organic Syrithesis-Methyl ester is then converted to a fully protected derivative by known methods. A preferred protecting group is a tert-butylcarbonyl (t-Boc) compound. This compound is prepared by reacting a 4-hydroxyprolimethyl ester with di-tert-butyl dicarboxylate in the presence of triethylamine and dimethylaminoPyridine to give a compound of formula XV.

The compound of formula XVI is prepared by oxidation of a compound of formula XV. A suitable oxidizing agent in this case is a mixture of ruthenium dioxide and sodium periodate. The oxidation is carried out in a multiphase mixture comprising the organic phase of the pyrrolidone compound (XV) in an organic solvent such as ethyl acetate, aqueous perioperbate salt solution and ruthenium dioxide. In about two days.

The amino and hydroxy protecting groups of the compound of formula XVI are removed to give the compound of formula XVII. Both protecting groups are usually removed by treating the compound of formula XVI with trifluoroacetic acid. This reaction is generally carried out at room temperature and is generally complete in about four hours.

The compound of formula (XVIII) is then converted to the compound of formula (IIIA) by essentially the method described above (Scheme II and commentary on Scheme II).

It will be appreciated that all of the above-described processes for the preparation of a compound of formula I include, as a last step, the hydrolysis of a compound of formula XIX

_CO2 ^R wherein R® hydrogen atom or a carboxyl protecting group, for example alkyl having 1-6 carbon atoms such as methyl or ethyl group, or arylalkyl group having I to 3 carbon atoms in the alkyl group such as a benzyl group, or a trimethyl group. The present invention therefore also relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising hydrolyzing a compound of formula (XIXI).

The compounds of formula (XIX) are believed to be novel and the invention also relates to them.

The compounds of formula I affect excitatory amino acid receptors. The invention therefore also relates to a method of affecting excitatory amino acid receptors in a mammal, wherein a mammal in need of modifying an excitatory amino acid receptors is administered a pharmaceutically effective amount of a compound of formula (I). The compound of the invention may be acting as an antagonist, partial arritagonist or agonist. When the compound of the invention acts as an arritagonist, it blocks EAA recePtor and therefore prevents receptor interaction with the Natural Ligand. If a compound of the invention acts as an agonist, the interaction of the compound with the EAA receptor mimics the response of the interaction of this receiver with its natural ligaride. (e.g., L-glutamate).

A certain dose of a compound of Formula I of the invention will always be determined by the physician, depending on the circumstances of the case being treated, such as the particular compound being administered, the route of administration and the condition being treated. The compounds or pharmaceutical compositions of the invention may be administered orally and rectally, trarisdermally, subcutaneously, intravenously, intramuscularly or intranasally. They may also be administered by continuous infusion. A typical daily dose contains the active ingredients of the invention from about 0.01 to about 100 tng / kg. A preferred daily dose contains the active ingredients of the invention from about 0.05 to about 50 mg / kg, and in particular from about 0.1 to about 25 mg / kg. - ·

It has been found that excessive or inappropriate stimulation of excitatory amino acid trarismise affects a variety of bodily functions. The compounds of formula I seem to be useful in the treatment of a variety of mammalian neurological disorders associated with inappropriate excitatory amino acid trasmission. surgical cardiac bypass, corpse, cerebral ischemia, spinal trauma, head trauma, perinatal hypoxia, cardiac arrest and hypoglycemic Řeuronal Damage - The compounds of formula I seem to be useful in the treatment of a variety of chronic neurological disorders such as Alzheimer's disease, Huntington's Chorea, Amyotropic Lateral Sclerosis »Dementia Induced by AOS, Eye Diseases and Retinoic Patients, Perception Disorders, Idiopathic and Drug-induced Parkinson's Disease-Compounds P According to the invention, they are suitable for the treatment of all such conditions, wherein a pharmaceutically effective amount of a compound according to the invention of the formula I is always administered.

It will be appreciated that the compounds of formula (I) are also suitable for the treatment of various other mammalian disorders associated with glutamate dysfunction, such as muscle spasm, migraine headache cramps, urinary incontinence, psychosis, opioid tolerance and withdrawal, anxiety , vomiting, brain swelling, chronic pain, and disciriesia The formula I compounds are also useful as analgesic and anti-depression agents. Thus, the compounds of the formula I are suitable for the treatment of such conditions, wherein a pharmaceutically effective amount of a compound of the formula I is always administered. Tests have been performed to demonstrate the ability of the compounds of formula I to influence excitatory amino acid receptorsAffinity for metabotropic glutamate receptors displacement 1S.3R-ACPD sensitive [³H] glutamate bonds to rat brain cell membranes. Bindings [³H] glutamate is carried out with crude rat forebrain membranes as described by SchoePP and True, (Schoepp and True, Neuroscierice Lett., 145, pp. 100-104, 1992; True and SchoePP, Society for Neuroscience Abstracts 19, p.470 (1993) and Wright, McDonald and SchoePP (J. Neurothem., 1994, 63, 938-945). Percent displacement³The H 3 -glutamate at a concentration of 100 µM of the compound of formula I is shown in Table II Table II

Peceptor binding of compound of formula Compound Percent displacement L- [ ³ H] Glu si number ³ (100 μΜ)

88.0 77, 1.8 2.4

66.5 82.3 δ

2 ο ->

L L

24d

3 2

38 44b 45b 46b 47b

53.9 7 2.0 52.3

85.8 77 Q

J -

86.7

81.6

93.8

85.9 76,9c

75.9

92.1

84.6

67.8

95.9

93.9

99.5

100.6c

98.5

82.1

66.5

97.8

89.0

93.7

99.4

92.6

90.1

95.3

92.4

81.3

89.9

103.2 101.5

85.5 107.1

48 91.9 49 81, 5 50 75.9 51 81.0

^{and the} test compounds is a mixture of enantiomers, unless otherwise indicated.

^b test compound is pure 2S, 4S enaritiotner ^c center of two or more tests ^d test compounds is a mixture of A and 8 isomers (A; 8 = 2.3: 1)

The affinity of the compounds of formula I for NMOA glutamate receptors is demonstrated by displacement of [3 H] CGS19755 binding to the synapt. rat forebrain osomal membranes. (Murphy et al., British J. Pharmacol., 95: 932-936, 1968). The general compounds of formula I produce a noticeable displacement of [ ³ H] CGS19755 when tested at a concentration of 100 mM.

The compounds of formula I according to the invention are preferably formulated into pharmaceutical compositions. The invention therefore also relates to pharmaceutical compositions comprising, as active ingredient, compounds of the formula I according to the invention together with pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical compositions of the invention are prepared by known methods using readily available ingredients. For the preparation of pharmaceutical compositions, the active compound of the formula I according to the invention is generally mixed with carriers or diluted with carriers or encapsulated in a carrier, which may take the form of a capsule, sachet, paper or other container. The pharmaceutical compositions may therefore take the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid). ointments containing, for example, up to 10% by weight of active ingredient, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Examples of suitable carriers, excipients and diluents are lactose. dextresis, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin. calcium silicate, m -rocrystalline Irish cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup, methylcellulose, methylhydroxybenzoate and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. or flavorings The pharmaceutical compositions of the invention may be formulated so that they rapidly, sustained or delayed release the active ingredient upon administration to a patient. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, generally about 25 to about 300 mg, of an active ingredient of formula (I). The unit dosage form herein refers to a physically discrete unit suitable for administration to humans; to other mammals, each such unit containing a predetermined amount of active ingredient calculated to produce the desired effect, together with a pharmaceutically acceptable carrier, diluent or excipient.

Hard gelatin capsules are prepared from the following ingredients:

Mouth (mg / cap 1 e)

3- (4-methylphenoxy) glutamic acid 250 starch, dried 200 magnesium stearate 10 total 460 mg

The ingredients are mixed and filled into hard gelatin capsules in an amount of 460 mg.

ó45

Example of pharmaceutical composition 2

Tablets are prepared from the following ingredients:

Amount of t knows (mg / t a a b 1 e t a)

3- (4- (1-Phenylhexylphenoxy) - glutamic acid 250 cellulose, microcrystalline 400 silicon dioxide, sublimated 10 , stearic acid 5 total 665 The components are mixed and they are compressed for tablets

weight 665 mg.

Example of pharmaceutical composition 3

The aerosol solution is prepared from the following components:

Mass

- (4- (1- (4-nitrosophenyl) ethenyl) * phenoxy) glutamic acid 0.25 ethanol 29.75 propellant 22 (chlorodifluoromethane) 70.00 total 100.00

The active ingredient is mixed with ethanol, and the mixture is introduced into a portion of the propellant 22 cooled to -30 ° C and transferred to a filling device. The required amount is filled into stainless steel containers or diluted with the remainder of the propellant. The packaging is provided with a valve.

Example of pharmaceutical composition 4

Tablets, each containing 60 mg of active ingredient, are prepared from the following ingredients:

Mr i (mg / t ab years)

- (5,6,7,8-tetrahydrate-2 diberisofuranoxy) glutamic acid 60,0 starch 45,0 cellulose, microcrystalline 35,0 polyvinylpyrrolidone (10½ solution in water) sodium carboxyroethylated starch stearate The talc which coats JX, 7. -. ^ .Ί. , Ί χ. · Ν.

χα ί-ί'-Ο, IJ · ^ Cl <^ ν_- xu j_t_A * LCI

4.0 4.5 0.5 1.0

150.0

-Č + · .- «m Μ. ι Λ R

U, S. (mesh diameter 355 microns) and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the obtained powder and the mixture is mixed with a No-14 mesh U-S sieve (diameter 1400 microns). 50 ° C through a No. 18 mesh U.S. sieve. (1000 micron mesh diameter) - Sodium carboxymethylated starch, magnesium stearate and talc are passed through a No. 60 mesh U.S sieve (250 micron mesh diameter). They are added to the granules, mixed and compressed to give tablets each weighing 150 mg.

PK Xd ΓΠ3Γ’.PU tLcP ¥ ^ * hO pKOStřPd ^ -U 5

Capsules, each containing 80 mg of active ingredient, are prepared from the following ingredients:

Quantity (mg / capsule)

3- (4- (1-Phenylpropyl-1-phenyl) phenoxy) glutamic acid 80 Starch 59 Microcrystalline cellulose 59 Magnesium stearate 2 Total 200

The active ingredient, starch and magnesium stearate are mixed, passed through a No. 45 mesh U.S. sieve. (mesh diameter 355 microns) a Filled into hard gelatin capsules in an amount of 200 mg each.

Example of pharmaceutical composition 6

Suppositories, each containing 225 mg of active ingredient, are prepared from the following ingredients:

Quantity (mg)

3- (2-naphthyloxy) glutamic acid 225 saturated fatty acid glycerides up to 2000

- .7 · 47

The active ingredient is passed through a No. 60 mesh U.S. sieve. (mesh diameter 250 microns) and suspended in saturated fatty acid glycerides

acids, pre-melted using the minimum heat required The mixture is poured into a suppository mold with a nominal capacity of 2.0 g to cool. lets Example of a pharmaceutical composition 7 Suspension, each containing 50 mg of active substance v 5,0 ml, se Prepares from the following ingredients: 3- (6-bromo-2-naphthyloxy) glutamic acid 50.00 mg sodium carboxymethylcellulose 50.00 mg syrup 1, 25 ml benzoic acid solution 0, 10 ml flavoring Ingredient q. v. dye q. in. purified water to 5.0 ml

The active substance is passed through a sieve. 45 mesh U.S. (mesh diameter 355 microns) and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. A solution of benzoic acid, flavoring and coloring agent, diluted with a little water, is added with stirring. Sufficient water is then added to achieve the desired volume.

The intravenous formulation is prepared from the following components;

3- (2-Fluoro enoxy) glutamic acid acid 100 ALIGN! mg mannitol 100 ALIGN! mg 5N sodium hydroxide solution him 200 ml purified water 5 ml

EXAMPLES The following examples illustrate the present invention in more detail. Dry tetrahydrofuran (THF) is prepared directly prior to use by distillation from sodium or sodium benzophenoriketyl. All other solvents and reagents are used in the process. Proton Nuclear Magnetic Resonance ( ¹ H NMR) spectra are obtained from a GE QE-300 spectrometer at 300.15 MHz and a Bruker AM-500 spectrometer at 500 MHz, or Bruker AC-200P at 200 MHz using a solvent. d6 ~ 0MSO unless otherwise noted. Mass atom bombardment (FABMS) is performed on the VG ZAB-2SE Instrument. Mass spectrometry of the desorption of the pellet is performed using either a VG 7OSE or Varian MAT 731. Optical rotation is measured with a Perkin-Elmer 241. Polarimeter. Chromatography separation is generally performed on a Waters Prep 500 LC using a linear gradient of the solvents listed above. in its termination by thin layer chromatography (TL..C). The r hrnmategrafii thinly ss applicability weighing Merck silikagolových plates 60 F ₂ 54 5 cm x 10 cm, 0.25 mm thick. A combination of UV and chemical detection is used to detect stains (platelets soaked in cerium ammonium molybdate solution [75 g of ammonium amide hydrate and 4 g of cerium sulphate in 500 ml of 10% aqueous sulfuric acid solution) and then heated on a hot plate. of Stilla et al., Still, Kahn and Mitra, J-Org. Chem. 43, p. 2923 (1978). Elemental analyzes for carbon, hydrogen, and nitrogen are performed on a Central Equjpment Corporation 440 Element Analyzer or at the Universidad Complutense Analytical Center (Facultad de Fartnacia, Madrid, Spain) - Melting points are determined in open glass capillaries on a Melting Temperature Instrument in a Gallenkamp hot air bath or on a Buchl melting point apparatus and are uncorrected - the number in parentheses after the compound name refers to either the compound number or the general formula.

Example 1

N-Benzyloxycarbonyl-2-oxa-3-aza-bicyclo [2.2.1] hept-5-ene (V)

Cycloperitadieri from dicycloperitadiene is distilled using a Vigreux column (8 cm), the distillate collected (boiling point 42).

C) in a cooled vessel (dry] ed / acetone) On a dry ice / acetone bath, stir methylene chloride (1000 mL) and treat with fresh distilled cyclopentadiene (59.6 g) and benzyl N-hydrocarbamate (166.5 g). ). The resulting solution was treated with a suspension of tetrabutylammonium periodinate (429 g) in methylene chloride (900 mL) at a rate such that the temperature remained below 3 ° C. After completion of the Periodic Suspension Additive (approximately 20 min. T.), The resulting mixture is stirred at rt. -5 ° C for two hours. Replace the ice / acetone bath with a dry ice / acetone bath that maintains a temperature of about -25 ° C to about -30 ° C by adding dry ice. Sodium bisulfite solution (340.5 g) is added. ) in water (1350 mL) at a rate such that the temperature of the reaction mixture was about -2 ° C to about 6 ° C. After about 50 minutes, the addition of sodium bisulfite was complete. The organic phase was separated and water (1050 ml) was added to the aqueous phase causing further separation of the organic and aqueous phases. The combined organic phases were washed with water (3 x 1600 ml) and saturated sodium bicarbonate solution (1050 ml), water ( 1600 ml) and 1N hydrochloric acid (1200 ml). The organic phase was dried over sodium chloride and magnesium sulfate, filtered and concentrated in vacuo to give 547.5 g of a brown solid. This solid was treated with diethyl ether (1400 mL) and the resulting mixture was filtered - the filtrate was evaporated to give a solid. (206.0 g). A solution of this solid in methyl ethyl chloride was added to silica gel (412 g) and the resulting mixture was evaporated to dryness. The title compound was isolated by flash silica gel filtration, eluting with hexari / ethyl acetate (4: 1, 4>). 3 liters) followed by hexari / ethyl acetate (2: 1, 6x3 liters) fractions containing the desired compound were combined and concentrated in vacuo to give a golden yellow oil. This oil was seeded with a solid sample of the desired compound to give 194.9 g of N-benzyloxycarbonyl-2-oxa-3-aza-bicyclo [2.2. 1] hept-5-ene as a solid Mass spectrum (FOMS): m / z = 231 (M ⁺ ) 1 H NMR (COCl ₃ ): d 7.31 (5H), 5.17 (4H), 2 01 (d, 1H), 1.75 (d, 1H) Analysis for C ₁₃ H ₁₃ NO ₃ :

calculated: C 67.52 found. C, 67.25

Example 2

H 5.67 N 6.06 H 5.69 N 5.96

N- &lt; / RTI &gt; oxycarbonyl-3,5-dicarboxy-1,2-oxazole (VI)

Prepare a solution of potassium permanganate by mixing potassium permanganate (123.2 g) in water (800 mL) at 55 ° C. After stirring overnight, the liquid is decanted. The residue is partially dissolved in water. water (100 mL) at 65 ° C. The solids were separated from the decantation solution and washed with water (50 mL). These solutions were combined for subsequent use. A biphasic mixture of the compound prepared according to Example 1 (69.4 g) in toluene (694 ml) and water (150 ml) was treated with tetrabutylammonium hydrogen sulphate (10.2 g). The resulting mixture was stirred with a mechanical stirrer, cooled down by partial immersion in an acetone / dry ice bath to about 2 ° C and treated with a potassium permanganate solution at a rate such that the temperature remained below 6 ° C. to freeze the aqueous phase. After 50 minutes, the addition of potassium permanganate solution is complete. The resulting suspension is stirred mechanically.

2.2 hours in an ice / water bath The reaction mixture was treated with Celite (348 g) and filtered through a dry Ceilite pad sealed to prevent channel formation. The solid was washed with ethanol / water (3600 mL, 4: 1). . The filtrate was concentrated in vacuo to a volume of approximately 400 mL. This concentrate was treated with water (100 mL) and ethyl acetate (600 mL). The pH of this mixture was adjusted to 0.81 by addition of 18 N sulfuric acid (110 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (500 mL, 400 mL). The combined organic extracts were. dried over sodium chloride and magnesium sulfate. The obtained N-benzyloxycarbonyl-3,5-decarboxy-1,2-oxazoline has a purity of approximately 85% and is used for the next reaction without purification by 1 H NMR. (COCl 3): d 7.3 1 (5H), 5.11 (2H), 4.71 q, 1H), 4.55 (t, 1H), 2.88 (m, 1H), 2.38 (m) (1H) (1) - (3-Benzyloxycarbonyl-5,5-dimethoxycarbonyl-1,2-oxazoline) (VII)

Resolution of crude N-benzyloxycarbonyl-3,5-di-carboxy-1,2-oxaine (compounds of Example 2) (79.5 g) in methylene chloride

1000 ml) was cooled to approximately -40 ° C in an acetonitrile / dry ice bath. This cold solution was treated with N, N-dilsoproylethylamine (68.7 g) for five. minutes. The cold solution was then treated with methylmethyloxonium tetrafluoroborate (8.5 g). The temperature of the reaction mixture was kept below -37 ° C by cooling in an acetonitrile dry ice bath. After about three hours, the reaction mixture was allowed to warm to -25 ° C and after one hour the cooling bath was removed. 500 ml) and the phases were separated. The organic phase was washed with sodium hydrogen sulphate solution (2400 ml, 1 x 200 ml). The organic phase was dried over sodium chloride, filtered, and concentrated in vacuo to give 81.18 g of the product. This product was dissolved in methylene chloride (600 mL) and worked on silica gel (153 g). Concentrate in vacuo to give a powder which is subjected to flash filtration. The desired compound is eluted with hexane / ethyl acetate (4: 1, 8 liters) followed by hexane / ethyl acetate (2: 1, 19 liters). containing the desired compound, were combined and concentrated in vacuo to give 49.4 g of N-benzyloxycarbonyl-3,5-dimethoxycarbonyl-1-oxazolirium as a yellow-orange oil, matt spectrum ( FDMS): m / z = 323 (M ^& lt ^{; +} & gt _; ). d 7.31 (5K), 5.12 (2H), 4.87 (q, t), 4.71 (t, i, 3.63 (d, 6H), 2.91 (m, 1H), 2.51 (m, IH).

z,. · ;: For C15H17NO7:

-counted '. C 55.73 H 5.30 N 4.33 Throwed: C 55.63 H 5.34 N 4.38.

t. ¹ lacI 4 '· ethyl-3-hydroxy-2-pyrrolidone-5-carboxylate. (IV)

Hydrogenate a mixture of the compound of Example 3 (73.1 g) and 10-Pmolecan on carbon (20.0 g) in tetrahydrofuran (600 mL) at a hydrogen train of 331.2 kPa at room temperature. After 18 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Analysis of the crude product (thin layer chromatography) indicated that the reduction was incomplete. The crude product was treated with 10% Palladium on carbon (6.0 g) and tetrahydrofuran (430 ml) and hydrogenated at room temperature. After 18 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting mixture was subjected to flash chromatography, eluting with a gradient of 10% hexane / ethyl acetate to 10% methanol / ethyl acetate-fractions containing. the desired compound, combined and concentrated in vacuo to give a brown oil. This oil was dissolved in acetone (90 mL) and the resulting solution was concentrated in vacuo. The residue was diluted with ethyl acetate (25 mL) resulting in immediate crystal formation. More ethyl acetate (25 mL) was added to the mixture. The crystalline material was collected by filtration and washed with ethyl acetate (50 mL). This material was dried under vacuum to give 11.54 g of the title compound. The filtrate was concentrated under vacuum until the second crop of crystals began to form. These crystals were collected by filtration and washed with ethyl acetate (10 mL) and dried under vacuum to give the title compound.

2.54 g of methyl 3-hydroxy-2-pyrrolidone-5-carboxylate, m.p. 85-86 ° C.

Mass spectrum (F OMS); m / z - 160 (M &^lt; ⁺ &^gt;; ) 1 H NMR; d 8.11 (c, 1H), J s.? t. (s, 1 H), 4.11 (dl, 1H), 3.62 ( _s , 3H), 2.29 (tn, 1H), 2.01 (m, 1 H). Analysis For C ^ HHgNOd calculated: C 45.28 H 5, 70 N 8.80 Found: C, 45.54 H 5, 70 N 8.54.

Example 5

Methyl 3- (2-methylphenoxy) -2-pyrrolidino-5-carboxylate (VIII)

A mixture of methyl 3-hydroxy-2-pyrrolidone-5-carboxylate compound

Prepared according to Example 4, (0.695g), triphenylphosphine (1.259g) and α-cresol (0.519g) in tetrahydrofuran (6.3mL) were cooled to 5 ° C and treated with a solution of diethyl azodicarboxylate ( 0.863 g) in tetrahydrofuran (1.8 mL) over six minutes. After the addition was complete, the reaction was allowed to warm to room temperature. After about 18 hours, the reaction solution was concentrated in vacuo. The residue was dissolved in a small volume of methylene chloride (4 mL) and purified by preparative thin layer chromatography, eluting with 50 X ethyl acetate / hexari followed by 75 X ethyllocetate / hexari - fractions containing the desired compound were combined and concentrated in vacuo to give 905 mg met.hyl-3- (2-methyl.ferioxy) -2-pyrrolidone ^_ 5-carboxylate, which contains triphenylphosphine oxide as impurity MS ( FDMS): m / z = 249

1 H NMR, d 7.12 (2H), 7.05 (1H), 6.83 (t, 1H), 4.84 (1H), 4.24 (1H), 3.66 (s, 3H) 2.88 (m, 1H), 2.08 ( _s , 3H), 1.99 (ΊΗ).

Example 6 3- (2-methyphenoxy) glutamic acid (4)

A mixture of lithium hydroxide (0.0939 g) in water (1.5 ml) and tetrahydrofuran (4.3 ml) was allowed to react. with methyl 3- (2-methylphenoxy) -2-pyrrolidone-5-carboxylate, prepared as in Example 5, (0.326 g) and warmed to about 62 ° C. After 4 hours, the reaction mixture was treated with 5N hydrochloric acid (784 mL). The resulting solution was concentrated in vacuo to an oily solid. This material was treated with tetrahydrofuran (v / v < 1x1, 10 mL) and the resulting insoluble material was collected. The solids were washed sequentially with the mixture. tetrahydrofuran / water (1: 1, 2 mL). water (3 mL) and tetrahydrofuran (10 mL). This material was dried under vacuum at 60 ° C for 18 hours to give 84 mg of 3- (2-methyphenoxy) glutamic acid

Mass spectrum (FABMS): m / z? = 254 ¹ H NMR: H 7.09 (2H), 6.81 (1H), 5.57 (1K), 4.77 (t, 1H), 3.66 (t, 1H), 2.19 ( m, 5H).

Example 7

Methyl-3- (2-naphthalenthlo) -2-pyrrolidone-5-carboxylate (VIII)

A solution of 3- (2-methylphenoxy) glutamic acid prepared according to Example 4 (0.553 g), triphenylphosphine <1.02 g) and 2-naphthalerithiol (0.474 g) in tetrahydrofuran (4.9 ml) was cooled. to a temperature of 0 C. This cold solution sp. treated with a solution of diethylazodicarboxylate (0.665 g) in tetrahydrofuran (1.4 mL) for one _ρ ΰ minuty- After complete addition the reaction was allowed to warm to místnosti- After approximately 23 hours, the solution in zkoriceritruje vakuu- Dilute the residue with methylene chloride. The insoluble material was removed by filtration and washed with methylene chloride (2 mL) and the filtrate was concentrated in vacuo. This residue was dissolved in a small amount of ethyl acetate and purified by PreParative thin layer centrifugal chromatography eluting with 50 X ethyl acetate / hexane followed by 75 X The ethyl acetate / hexane fractions containing the desired compound were combined and concentrated in vacuo to give 416 mg of methyl 3- (2-naphthalenthio) -2-pyrrolidone-5-carboxylate containing triphenylphosphiroxide as an impurity. Mass spectrum (FDMS): m / z = 301

Example 3

3- (2-Naphthalenthlo) glutamic acid (24A and 24 &)

A mixture of methyl 3- (2-naphthalenothio) -2-pyrrolidone-5-carboxylate, a compound prepared according to Example 7 (1.53 g) in tetrahydrofuran (14.5 ml) and water (5.1 ml) The reaction mixture was allowed to cool to room temperature. After approximately 3 1/3 hours, the reaction mixture was allowed to cool to room temperature. After an additional hour, the reaction mixture was treated with 5N hydrochloric acid (3.04 mL). The resulting solution was placed in a freezer overnight. The solution was partially concentrated in vacuo to remove tetrahydrofuran and the residue was extracted with methylene chloride (3 x 20 mL). The aqueous phase is loaded onto a cation-exchange chromatography column (OOWEX 5OX-8). The column was washed sequentially with water (200 mL), 50% tetrahydrofuran / water (200 mL) and water (200 mL). The desired compound was eluted with 10X pyridine / water. the fractions containing the desired compound were combined and concentrated in vacuo to a volume of approximately 70 mL. to initiate crystallization. The crystalline material was collected by filtration, washed with water, and dried at room temperature with phosphorus pentoxide to give 307 mg of a mixture of diastereomers (A / B = 2.3: 1). crystals The crystals were collected by filtration and washed with water. The filtrate was evaporated to dryness in vacuo to give 250 mg of a mixture of diastereomers (B / A = 2.3: 1).

Compound 24A

1 H NMR: d 7.83 (m, 3H), 7.51 (m, 4H), 4.34 (t, 1H), 3.50 (t, 1H),

2.22 (m, 1 H), 1.91 (m, 1 H).

Analysis for C 15 H 15 NO 4 S:

calculated: C 59.00 H 4.95 N 4.59 S 10.50 found: C 59.19 H 4.83 N 5.38 S 10.30.

P .1 o u r u n d 2 4 B

FABMS: m / z ~ 306 (M @ ⁺ +1)

1 H NMR- d 7.83 (m, 3H), 7.47 (m, 4H), 4.23 (m, 1H), 3.58 (1H),

2.01 (m, 2 H).

Example S

3-Phenoxyglutamic acid (1)

3-Phenoxyglutamic acid was prepared essentially as described in Examples 5 and 6, except that phenol was used.

FABMS: m / z = 240 (M + 1, 221 (M-H ₂ O)), 195 (M-CO ₂ ) 1 H NMR: d 7.22 (t, 2H), 6.88 (t 1H), 6.74 (d, 2H), 4.75 (t, 1H),

3.63 (t, 1H), 2.22-2.08 (m, 2Η).

Analysis. strip C i H 3 NO 5:

calculated: C 55.2.3 H 5.48 N 5.86 loaded: C 55.23 H 5.27 N 5.72.

Example 10

Acid 3 -ber ixent.h 1 og lu tensile (2)

3-Benzerithioglutamic acid was prepared essentially as described in Examples 5 and 6, except that thifrifenol was used. Mass Spec. (FARMS): m / z ~ 256 (M + 1), 237 (MH ₂ O) 1 H NMR: d 7.42 (d, 2H), 7.27 (m, 3H), 4.21 (t, 1H), 3.43 (1H),

2.16 (m, 1 H), 1.84 (m, 1 H).

3- (4-Methylphenoxy) glutamic acid (3)

3- (4-Methylphenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that β-cresol was used. 3- (4-Methylphosphoryl) glutamic acid was purified by cation exchange chromatography (OOWEX 5OX-). 8) eluting with 10 &apos; Pyridine / water mass spectrum (FABMS) system. m / z. 254 (M + 1), 235 (MH ₂ O), 164 (M + 1-CO ₂ ).

1 H NMR: d 7.00 (d, 2H), 6.72 (d, 2H), 4.89 (q, 1H), 3.96 (m, 1H), 2.14 ( _s , 3H), 2 34 (t, 2H). Example 12

3- (4-Methoxyphenoxy) glutamic acid (5)

3- (4-Methoxyphenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 4-methoxyphenol was used. Mass Spectrum (FABMS): m / z = 270 (M + 1).

1 H NMR: δ 6.77 (m, 4H), 4.68 (t, 1H), 3.62 (m, 4H), 2.15 (m, 2H)

H, 5.6; N, 5.20. Found: C, 53.26; H, 5.55; N, 4.98.

Ořiklad 13

3- (4- (Isopropyl) tertioxy) glutamic acid (6)

3- (4- (Isopropyl) phenoxy) glutamic acid is prepared essentially as described in Examples 5 and 6, except that

Use 4-isopropylphenol.

Mass spectrum (FABMS) 1 H NMR: d 7.09 (<1, 2H), 2.76 (1H), 2.23-2.07 (m, m / z = 282 (M + 1)).

6.67 (d, 2H), 4.71 (1H), 3.61 (1H), 2H), 1.12 (d, 6H).

Analysis for Ci ^ HigNOs:

calculated: 0 59.78 H 6, 81 N 4.98 found; C 59.17 H 6, 69 N 4.84

Example 14

3- (4-Hydroxy-pentyl-phenoxy) -glutumic acid (7)

3- (4-Cyclopentylphenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 4-cyclopentylphenol was used Mass Spectrum (FABMS); m / z = 308 (M + 1), 217 (M-CO 2)

1 H NMR; d 7.10 (d, 2H), 6.68 (d, 2H), 4.73 (t, 1H), 3.63 (t, 1H),

2.84 (1H), 2.18 (m, 2H), 1.93 (2H), 1.57 (6H).

Analysis calculated for C 1 H 2 O 5 NO 5; C 62.53 H 6.89 N 4.56 Found: C 62.61 H 6.89 N 4.60.

Example 15

3- (4- (1,1,3,3-tetramethylbutyl) phenoxy) glutamic acid (8)

3- (4- (1,1,3,3-tetramethylbutyl) phenoxy) 91uumic acid was prepared essentially as described in Examples 5 and 6, except that 4- (t-octyl) was used. phenol 3- (4- (1,1,3-3-tetramethylbutyl) phenoxy) glutamic acid was purified by cation exchange chromatography (DOWEX 5OX-8) eluting with 10% pyridirm / water Mass Spec (FABMS): m m / z - 352 (M + 1). 308 (MH + H-CO 3) 1 H NMR. d 7.24 (d, 2H), 6.67 (d, 2H), 4.72 (1H), 3.63 (1H), 2.23-2.06 (brtn, 2K), 1 65 (2H), 1.26 ( _a , 6H), 0.65 (s, 9H). Analysis for C19H29NO5:

calculated; C 64.94 H 8.32 N 3.99 Found: 0 65.12 H 8.47 N 3.82.

.Example 16

3- (4-Acetylphenoxyl) glutamic acid (9)

3- (4-Acetylferioxyl) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 4-hydroxylation of Lofertone Mass Spectrum (FABMS) was used; m / z = 282 (M + 1).

1 H NMR: (d 6 -DMF): d 8.08 (d, 2H), 6.93 (d, 2H), 5.06 (t, 1H), 4.12 (t, 1H), 2.53 ( _s , 3H), 2.49 (m, 2H).

Example 17

3- (4-Trifluoromethylphenoxy) glutamic acid (10)

The 3- (4-trifluoromethylphenoxy) glutamic acid is prepared essentially as described in Examples 5 and 6 _{, with} the exception that 4-1 fluorofluoromethylphenyl is used.

Mass Spectrum (FABMS); m / z = 308 (M + 1).

1 H NMR: d 7.59 (d, 2H), 6.93 (d, 2H), 4.87 (t, 1H), 3.70 (t,

1H), 2.21 (bm, 2H).

Analysis for C12H12NO5:

H, 3.94; N, 4.56. Found: C, 47.12; H, 3.93; N, 4.49.

and

Example 13

3- (3,4-Dichlorophenoxy) glutamic acid (11)

LNA acid; 3- (3,4-dich'l.orferwxv) 9lutamová prepares vp d _-J essays in the manner described in Examples 5 and 6 except that the use ž1j e 3,4-di ch1orofeno1u

FABMS: m / z = 303 (M + 1).

@ 1 H NMR. d 7.45 (d, 1H), 7.05 (d, 1H), 5.30 (dd, 1H), 4.81 (t

1H), 3.69 (t, 1H), 2.21 (m, 2H).

Analysis for C11H11NO5:

calculated: C 42.88 H 3.60 N 4.55 loaded: C 42.36 H 3.67 N 4.35.

Example 19

3- (4-Phenylphenoxy) glutamic acid (12)

3- (4-Phenylphenoxy) gl utaffinic acid was prepared essentially as described in Examples 5 and 6 except that 4-phenylphenol was used. Mass spectrum (FABMS): m / z = 316 (M + 1) ).

1 H NMR: d 7.55 (4H), 7.40 (t, 2H), 7.26 (t, 1H), 6.86 (d, 2H),

4.63 (1H), 3.67 (1H), 2.30-2.16 (m, 2H).

Analysis for C ^ HHiyNOc ,:

calculated: C 64.76 H 5.43 N 4.44. Found: C 65.01 H 5.44 N 4.34.

Example 20

Acid. Flax 3- (3-phenylphenoxy) glutamic (13)

The 3- (3-phenylphenoxy) glutamic acid is prepared essentially.

as described in Examples 5 and 6 except that 3-phenylphenol was used

FABMS: m / z ~ 316 (M + 1).

1 H NMR: d 7.55 (2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.18- (d, 1H),

7.02 (s, 1H), 6.84 (d, 1H), 6.75 (dd, 1H), 4.86 (t, 1H), 3.65

(t, 1H), 2.32-2.10 (m, 2H). Analysis for O 17 H 17 NO i ie calculated: C 64.75 H, 5.43 N 4.44 Found: C, 64.79 H, 5.41 N 4.43

Example 21

3- (4-Benzylphenoxy) glutamic acid (14)

3- (4-Benzylphenoxy) glutamic acid is prepared essentially

as described in Examples 5 and 6 with that lives 4-hydroxydiphenylmethane- except that I pnuck Mass Spectrum (FABMS): m / z = 330 MM + n \ '' · z ^w 1 H NMR: d 7.26-7.07 (7H), 6.69 (d, 2H), 4 72 (t, 1 H), 3.62

(1H), 2.27-2.06 (m, 2H).

n ί. -i i o r r £

3- (2-Benzylphenoxy) glutamic acid (15)

3- (2-Bertzylphenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6, except that 2-hydroxydiphenylmethane was used. Mass Spectrum (FABMS): m / z = 330 (M + 1), 311 MH + 0 ).

¹ H NMR: d 7.21 (4H), 7.10 (3H), 6.81 (t, 1H), 6.60 (d, 1H),

4.78 (t, 1H), 3.89 (q, 2H), 3.63 (t, 1H), 2.28-2.15 (m, 2H).

Analysis for CtgHigNOs:

H, 5.81; N, 4.25. Found: C, 65.40; H, 5.69; N, 4.05.

Example 23

3- (4- (6-Fertyhexyl) phenoxy) glutamic acid (16) (i) A mixture of 1,4-dibenzoylbutane (119 g) and 5Ž palladium on carbon (15.0 g) in ethyl acetate (1.355 L) and concentrated acid sulfuric acid (11.3 mL) was hydrogenated at 50 psi hydrogen pressure. After three hours, the reaction mixture was allowed to cool to room temperature. The mixture was treated with water (2 x 500 mL) and the phases were separated. The organic phase was washed with 10% aqueous sodium hydrogen tartrate (250 mL). The organic phase was dried over sodium chloride, filtered and concentrated in vacuo to an oil. It is subjected to vacuum distillation. Distillation at 141-151% (0.031992 kP) resulted in 119 g of 1,6-di-difluorohexane as a colorless oil.

1 H NMR: d 7.26-7.21 (4H), 7.15-7.11 (6H), 2.5? (t, 3H), 1.54-1.48 (4H), 1.30-1.26 (4H).

(ii.) A solution of 1, 6-difenylhexariu (119.05 g) and acetic anhydride (50.98) in 1, 1, 2,2-tetrachloroethane (375 mL) was cooled to approximately ^- 38 ° C in a bath acetori / dry ice was added to the solution at such a rate that the temperature remained below 9 ° C. At the end of the addition of aluminum chloride (about 80 minutes), the resulting reaction slurry was allowed to warm to room temperature. the reaction mixture was cooled to about 0 ° C in a water / ice bath and then. is treated with 6N 6N hydrochloric acid (150 m () at a rate such that the temperature remains below 8 ° C. The reaction mixture was treated with water (500 mL) and the phases were separated. The aqueous layer was treated with chloroform (3 x 250 mL) and the phases were separated. The combined organic phases were washed with water (250 mL), dried over sodium chloride, filtered and concentrate in vacuo to an oil which solidifies on standing. A solution of this solid in methylene chloride is subjected to vacuum distillation at room temperature. 200-210 ° C (0.01333 kPa) to give 61.45 g of 4 '- (6-phenylhexyl) acetophenorium as an oil. 1 H NMR: d 7.84 (d, 2H), 7.30 (d (2H), 7.26-7.21 (2H), 7.15-7.10 (3H), 2.60 (t, 2H), 1.52 (5H), 1.56-1.50 ( 4H), 1.29 (4H).

(iii.) A biphasic solution of 4 '- (6-phenylhexyl) -ethanol orion (61.36 g) and m-chloroperoxybenzoic acid (166.15 g) in methylene chloride (550 mL) was heated to reflux. (Note: the chloroperoxybenzoic acid used in this reaction is a 1: 1 mixture of m-chloroperoxybenzoic acid and m-chlorobenzoic acid). After 22 his ^- ddnách reaction mixture was allowed to cool to room temperature

The reaction mixture was filtered and the insoluble portion was washed with methylene chloride (50 ml). Water (250 ml) was added to the filtrate. The pH of the biphasic solution was adjusted from 3.34 to 5.98 with 5N sodium hydroxide solution (14 ml). ml). To the biphasic solution crushing water (3 µl) was added and the mixture was purged with uranium dioxide and treated with an additional potassium carbonate solution (2.times.50 ml) and then with brine (3.times.500 ml). dried over sodium chloride, then magnesium sulfate, filtered, and concentrated in vacuo to give a semi-crystalline solid.

After about 15 minutes at room temperature, the isolated material exotherms. Approximately 10 minutes later a brown oil appeared. The oil-methylene chloride solution (1 L) was washed with saturated aqueous sodium bicarbonate (3 x 500 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. til l L Ujk Si:

,>. ......

v ti vcUmju z. a * z_ i i J. '·· u

48.46 g

F _ f Λ ___ 4 * j-,. 1 K *. 1,1,1 '-. . ~ t V ir; nyi * <A y i. j ¹ οι iy □. rpm in the form of an oil.

(iv) To a mixture of 4- (6-phenylhexyl) ferrylacetate in methanol (62.0 mL) and water (550 mL) was added sodium carbonate (71.86 g.) The resulting suspension was refluxed. After 1.5 hours, the reaction mixture was concentrated in vacuo to remove most of the methanol contained therein. More water was added to the reaction mixture, and the reaction mixture was then treated with diethyl ether (4 x 500 mL). The combined organic phases were washed with 1N hydrochloric acid (3 x 100 ml), dried over sodium sulfate and filtered. 70 mesh US mesh 230-400 (mesh width 63-38 µm) was added to the filtrate (70 and evaporated). The title compound was isolated by flash silica gel chromatography eluting with a system of ethyl acetate / ethyl acetate / ethyl acetate (I (1: 0.00125, 4 x 250 ml) followed by a system of he (1: 1,4, 4 x 250 ml) and finally hexane / 0.15, 4 x 250 mL) The fractions containing 1- (4-hydroxy-oxyphiyl) -6-phenylhexari were combined and concentrated in vacuo to give 20.42 g of an oil on standing at room temperature. oil outcrop

t.aluje

Mass spectrum (FOMS): m / z = 254

1 H NMR: d 9.06 (1H), 7.23 (2H), 7.13 (3H), 6.92 (2H), 6.61 (2H),

2.61 (t, 2H), 2.40 (t, 2H), 1.56-1.41 (4H), 1.31-1.24 (4H).

(v) A mixture of the compound prepared according to Example 4 (3.612 g), triphenylphosphine (6.7 59 g) and 1- (4-hydroxyphenyl) -6-phenylhexane (6.555 g) in Letrahydrofuran (3 2 ml) is cooled to approximately. 1-2 ° C and treated with a solution of diethyl azodicarboxylate (4.080 g) in tetrahydrofuran (10 mL) for 17 min. After the addition was complete, the reaction suspension was allowed to warm to room temperature. After about 24 hours, the resulting brown solution was concentrated in vacuo. The residue was diluted with chloroform (10 mL), the insoluble material was collected by filtration, and the filtrate was concentrated in vacuo. Dissolve in methylene chloride and add silica gel US mesh 230-400 (mesh width 63-38 µm) (36 g). The reaction mixture was concentrated in vacuo to give prášku- mixture was subjected to flash silica gel chromatography eluting with hexari / ethyl acetate (5: 2, 10 x 200 mL), _t p and with hexane / ethyl acetate (5: 3, 7 x 100 mL , 1 x 200 ml), then ethyl ether (10 x 200 ml) and finally ethyl acetate (2 x 200 ml, 2 x 500 ml). The fractions containing the desired product were concentrated in vacuo to give a gold oil. The gold oil was dissolved in methylene chloride (24 mL) and purified by preparative thin layer centrifugal chromatography (4 mm plate, flow rate 8 mL / min) eluting with a 50 mL system. % ethyl acetate / hexane until the first lane eluted, then the solvent was changed to ethyl acetate. Fractions containing methyl 3- (4- (6-hexylphenyl) phenoxy-3-pyrrole-cake-5-carboxylate) were combined and concentrated in vacuo to give a gold. The oil was dissolved in diethyl ether (10 mL) and hexane was added until the solution became cloudy.After 45 minutes at room temperature, the cloudy solution was concentrated, concentrated in vacuo to form a solid product, and diethyl ether (10 mL) was added to the product. the insoluble matter was removed by filtration. The filtrate was concentrated in vacuo to an oil which crystallized out - diethyl ether was added to the crystalline material. Stir 30 minutes64

Insoluble materials were collected by filtration to give 3.91 g of methyl 3- [4- (6-r, exylphenyl) phenoxy] -2-pyrrolidone-5-carboxylate.

1 H NMR: d 8 = 54 (1H), 7.23 (2H), 7.13 (3H), 7.04 (2H), 6.85 (2H), 4.83 (1H), 4.21 ( t, 1H) _: 2.89 (m, 1H), 2.54-2.37 (4H), 1.88 (m, 1H), 1.56-1.44 (4H), 1.23- 1.14 (4H), (vi) A mixture of lithium hydroxide (0.712 g) in water (9.3 ml) and tetrahydrofuran (29 ml) was treated with methyl-3- [4- (6-hexylphenyl) phenoxy-3-pyrrolidinone]. -5-carboxylate (3.91 g) and maintained at 58 ° C with heating. After about 3.8 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was then treated with 5N hydrochloric acid (5.84 mL). The resulting light suspension was stirred and then stirred at room temperature for 15 minutes. Insoluble matter was collected by filtration, washed with 1: 1 tetrahydrofuran / water (10 mL) and finally water (10 mL). The title compound crystallizes from the filtrate and is collected by filtration. This product is dried under vacuum to give the title compound (1.077 g). Analysis for C23H29NO5:

Calculated: C 69.15 H 7.32 N 3.51 Found: C 69.32 H 7.29 N 3.30.

FDMS: m / z = 400 (M + 1), 382 (M + 1 H 2 O)

1 H NMR: d 7.22 (2H), 7.11 (3H), 7.02 (d, 2H), 7.65 (d, 2H), 4.70 (q, 1H), 3.61 (q) (1H), 2.50 (1H), 2.14 (m, 2H), 1.47 (m, 5H),

1.22 (m, 5H).

Example 24

3- (4- (3-Phenylprop-2-enyl) phenoxy) glutamic acid (17)

3- (4- (3-phenylprop-2-onyl) phenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6, except that 3- (4-2-hydroxyphenyl) -1 was used. -phonylprop-1-enu Mass spectrum (FABMS): m / z - 356 (M + 4).

1 H NMR: d 7.37 (2H), 7.27 (3H), 7.15 (2H), 6.72 (2H), 6.38 (2H),

4.74 (t, 1H), 3.63 (q, 1H), 3.42 (2H), 2.17 (m, 2H).

.]

Example 25

It was found to be 3- (4- (2- (4-nitrophenyl) ether) (1) phenoxy) gutamate (18)

3- (4- (2- (4-Trophenyl) ethenyl) phenoxy) glutamic acid

Prepared essentially as described in Examples 5 and 6, except that 1- (4-hydroxyphenyl) -2- (4-nitrophenyl) ether was used Mass spectrum (FABMS): m / z = 387 (M +) 1), 341 (M + 1-NO ₂ ).

1 H NMR: d 8.19 (d, 2H), 7.80 (d, 2H), 7.58 (d, 2H), 7.23 (d, 2H),

6.62 (d, 2H); 4.84 (t, 1H); 3.69 (1H); 2.21 (m, 2H);

Analysis for C ₂ q ₂ iN0s: Cld: C 67.59 H 5.96 Found: C 67.29 H 5.89

N 3.94 N 3.74.

Example 26

3- (4-Phenoxy-phenoxy) -glutamic acid (19)

3- (4-Ferioxyphenoxy) g-1-utamic acid was prepared essentially as described in Examples 5 and 6, except that 4-phenoxyphenol was used.

FABMS: m / z = 331 ([delta]), 313 (MH _&lt; 0 &gt;).

¹ H NMR 7.29 (2H), 7.02 (1H), 6.96-6.74 (6H), 4.73 (Ί, 1H),

3.64 (t, 1H); 2.29-2.08 (m, 2H).

H, 5.17; N, 4.23. Found: C, 61.81; H, 5.12; N, 4.21.

Example 27 3- (4-Berizyloxyoxyphenoxy) glutamic acid (20)

3- (4-Benzyloxy-phenoxy) -glutamic acid was prepared essentially as described in Examples 5 and 6 except that 4-benzyl-oxyphenol was used Mass spectrum (FABMS): m / z - 346 (M + 1) , 256 (M + 1-CO ₂ ).

H, 5.45; N, 4.06

Found: C 62.61 H 5.67 N 3.97.

Example 28

3- (2-Naphthyloxyl) glutamic acid (2 i)

3 '(2-naphthyloxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 2-afto-1 was used. Mass spectrum (FABMS): m / z 1H NMR: d 7.76 (3H), 7.40 (t 7.01 < d, 1H), 4.94 (t, 1H), &lt; 2 &gt; calculated: 0 62.28 H 5.23 N found: C 61.98 H 5.22 N = 290 (M + 1).

1 H, 7.30 (t, 1 H),

40-2.15 (m, 2 H).

4.64

4.66.

(dd, 1 H),

Example 29

3- (6-Bromo-2-riaphthyloxy) glutamic acid (22) (i) Compound mixture Prepared as. described in Example 4 (0.498 g), triphenylphosphine (0.932 g) and 6-bromo-2-naphthol (0.793) in tetrahydrofuran (4.3 mL) were cooled to about 1-2 ° C and treated with a solution of diethyl azodicarboxylate (0.619 g) ) in tetrahydrofuran (4.3 mL) for one minute. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After about 23 hours, the solution was concentrated in vacuo. The residue was diluted with chloroform (2 mL), the insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. flow rate = 8 mL / min) eluting with hexane / ethyl acetate (1 L) until the first lane eluted, then the solvent changed to hexane / ethyl acetate (1: 3). The fractions containing the desired product were combined and concentrated in vacuo to give methyl 3- (6-bromo-2-riaphthyloxy) -2-pyrrolidone-5-carboxylate (778 mg).

Mass spectrum (FABMS): m / z - 363.365 ¹ H NMR: ₍ δ 8.63 ( _s , 1H), 8.09 ( _s> 1H), 7.81 (d, 1H), 7.73 (d, IH)

7.61 to 7.45 (IH + 0 = _PPh3), 7.42 (IH), 7.21 (dd, 1H), 5.04 _(t) 1H), 4.26 (t, IH), 3.65 ( ₃ , 3H), 3.09-2.99 (m / z).

IH), 1.92-2, 01 (m, 1H). in water (2.0 ml) and tet 3- (6-Bromo-2) -naphthyloxy) and warming up keeps ria , reaction the mixture is left the mixture is then processes

Insoluble matter from 1 tetrahydrofuran / water (10

Separate by filtration with 5N hydrochloric acid (1.30 ml), washing with 1:

ml), tetrahydrofuran (10 ml) and water (5 ml). The insoluble material was dried overnight at 60 ° C in a vacuum oven to give 3- (6-bromo-2-naphthyloxy) glutamic acid.

Mass spectrum (FOMS): m / z = 368.350 (MH ₂ O)

1 H NMR: d 8.06 ( _s , 1H), 7.76 (2H), 7.50 (dd, 1H), 7.18 (dd, 1H), 7.05 (d, 1H), 4.94 (t, 1H), 3.70 (1H), 2.30-1.70 (m, 2H),

Analysis for C15Hq4BrNO5:

calculated: C 48.93 H 3.83 found. C 48.65 H 3.81

N 3.80 N 3.66.

Example 30

3- (1,6-Dibromo-2-naphthyloxy) glutamic acid (23)

3- (1,6-Dibromo-2-naphthyloxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 1,6-dibromo-2-naphthol was used. Mass Spectrum (FABMS): 447,368 (M-8r) 1 H NMR: d 8.17 (1H), 7.99 (d, 1H), 7.89 (d, 1H), 7.70 (dd, 1H),

7.18 (d, 1H), 5.03 (t, 1H), 3.78 (t, 1H), 2.30 (m, 2H).

Analysis for C 15 H ₁₃ BrNO ₃ :

calculated: C 40.30 H 2.93 N 3.14 found: C 40.35 H 2.92 N 3.11,

- 68 Example 31

3- (1-Naphthyloxy) -gamic acid 3- (25)

3- (1-Naphthyloxy) glutamic acid was prepared in the administration as described in Examples 5 and 6, except that 1-naphthol was used. Mass Spectrum (FA&MS): m / z = 290 (M +) 1).

¹ H NMR: d 8.18 (1H), 7.85 (1K), 7.49 (3H), 7.35 (t, 1H), 6.64 (d, 1H), 4.99 (t, 1 H, 3.75 (t, 1 H), 2.36 (m, 2 H),

Analysis for Cii5NQ5:

H, 5.23; N, 4.84. Found: C, 62.49; H, 5.15; N, 4.80.

Example 32

3- (5,6,7,8-Tetrahydro-1-naphthyloxy) glutamic acid (26)

3- (5,6,7,8-tetrahydro-1-naphthyloxy) -gutamic acid was prepared essentially as described in Examples 5 and 6, except that 5,6,7,8-tetrahydro-1 was used. -naphthol Mass spectrum (FA6MS): m / z - 294 (M + 1), 250 (M + 1-CO 2) -

1 H NMR: d 6.95 (1H), 6.62 (d, 1H), 6.36 (d, 1H), 4.72 (1H), 3.64 (1H), 2.65-2.10 (brm, 6H), 1.67 (4H), Analysis for C15H19NO5: C, 61.42; 6.53 N 4 , 78 Found: C, 61.40 H 6.43 N 4 , 73.

Example 33

3- (6,7-Dihydro-5,5,8,8-tetramethyl-2-riaphthyloxy) glutamic acid (27)

3- (6,7-Dihydro-5,5,8,8-tetramethyl-2-naphthyloxy) glutamic acid was prepared essentially as described in Examples a and 6 except that 6,7-dihydro- 5,5,8,8-tetramethyl-2-naphthol.

FABMS: m / z = 350 (M + 1).

1 H NMR: δ 7.18 (d, 1H), 6.96 (1H), 6.50 (1H), 4.71 (1H),

3.61 (1H), 2.44 to 2.07 (b _r m, 2H), 1.57 (4H), 1.17 (12H).

H, 7.79; N, 4.01. Found: C, 65.47; H, 7.89; N, 3.95.

Example 34

3- (5-Indanyloxy) glutamic acid (28)

3- (5-indanyloxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that the 5-indanol mass spectrum (FABMS) was used: m / z = 280 (M + H).

1 H NMR: d 7.06 (d, 1H), 6.63 (3, 1H), 6.54 (dd, 1H), 4.71 (1H),

3.62 (1H), 2.75 (m, 4H), 2.44-2.07 (m, 2H), 1.96 (2H).

Example 35

3- (3,4-methylenedioxyphoxy) glutamic acid (29)

3- (3,4-Methylenedioxyphoxy)) glutamic acid was prepared essentially as described in Examples 5 and 6 except that 3,4- (methylenedioxy) phenol was used.

1 H NMR: d 6.74 (d, 1H), 6.48 (d, 1H), 6.17 (dd, 1H), 5.90 (s, 2H), 4.64 (q, 1H), 3 59 (q, 1H); 2.20-2.04 (m, 2H).

Example 36

(I) A mixture of the compound prepared as described in Example 4 (0.462 g), triphenylphosphine (0.864 g), and 2 - (2 - fluorophenoxy) g. -hydroxyfluorone (0.600 g) in tetrahydrofuran (4.2 mL) was cooled to about 1-2 ° C and treated with a solution of diethyl azodicarboxylate (0.573 g) in tetrahydrofuran (1.7 mL) for five minutes. After stirring at 70 ° C for 24 hours, the resulting suspension was filtered and the insoluble material was washed with tetrahydrofuran (5 ml) to give 0.526 g of methyl 3- (2-fluorophenoxy) -2-pyrrole. > 1 idon-5-carbohydrate which is dried in a vacuum oven At 60 ° C for approximately 24 hours Mass spectrum (FDMS): m / z - 323

1H nmr _; 3.53, 7.18 (2H), 6.97%, (d, 1H),

7 5 (A 7Mi • y 'a 5 - · p

4.95 (t, IH)

7.50 (d, 4.24 (t,

1H 17 77 ft 1H>

• 'Z'? - '\ c- · · · · z

1H), 3.81 (s, 2H)

3.65 (s, 3H)

3.00-2.90 (rn,

1H),

1.98-1.90 (m, IH).

(11) A mixture of lithium hydroxide (0.117 g) in the _{Q e} ga (1.5 mL) and tet "rahydrofuranu (4.7 ml.) Was treated with methyl 3- (2-fluorenoxy) -2-pyrrolidone-5-carboxylate ( 0.526 g) and kept on a 60 ° C wallpaper by heating. After about 3.3 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was then treated with 5N hydrochloric acid (976 mL). The resulting colloidal suspension was stirred for 10 minutes. Nerrizpust ^r> E pnd.íly collected by filtration, washed with 1: 1 tetrahydrofuran / vrjda (10 mL), tetrahydrofuran ur act (10 mL) and water (10 mL). The insoluble material was dried overnight at 60 ° C in a vacuum oven to give 3- (2-fluorenoxy) glutamic acid.

Mass Spectrum (FOMS); m / z - 328 (M + 1) ¹ H NMR; d 7.73 (d, 2H), 7.46 (cl, 1H), 7.29 (t, 1H), 7.19 (t, 1H) 6.98 (dd, 1H); 6.81 (dd, 1H); 4.83 (t, 1H); 3.82 (s, 1H); 3.67 (q, 1H); 22 (bm, 2 H).

Analysis For C 18 H 17 NO 5;

H, 5.24; N, 4.28. Found: C, 65.63; H, 5.30; N, 4.21.

Example 37

3- (2-Dibenzofuranoxy) glutamic acid (31) (i) A mixture of the compound prepared as described in Example 4 (1,450 g) and 2-hydroxybenzofuran

4- J f Ί í <, r. » i 1 'ř 1 1

See J., J.-l. (1.019 g) in tetrahydrofuran (7.0 mL) was cooled to about 2 ° C and treated with a solution of diethyl azodicarboxylate (0.963 g) in tetrahydrofuran (2.0 mL) for two minutes. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After about 15.5 hours, the solution was concentrated in vacuo. The residue was diluted with toluene (5 mL), the insoluble material was collected by filtration, and the filtrate was concentrated in vacuo. The oil was dissolved in ethyl acetate and the product was purified, 1. ml / min) eluting with hexane / ethyl acetate (1: 1) until the first lane elutes, then the solvent is changed to hexane / ethyl acetate (1: 3).

Fractions containing the desired compound were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 1-3- (2-dibertzofuranoxy) -2-pyrrolidone-5-carboxylate (427 mg) which contains triphenylphosphine oxide as an impurity ·

Mass spectrum (FOMS): m / s = 325

1 H NMR: d 8.60 ( _s , 1H), 8.07 (d, 1H), 7.75 (d, 1H), 7.64-7.45 (3H + O-PPh ₅ ), 7.35 (t, 1H), 7.13 (dd, 1H), 4.97 (t, 1H), 4.26 (t, 1H), 3.65 (s, 3H), 3.05-2.95 ( m, 1H), 2.03-1.94 (m, 1H).

(ii) A mixture of lithium hydroxide (0.0943 g) in water (1.4 mL) and tetrahydrofuran (4.3 mL) was treated with methyl 3- (2-dibonzofuranoxy) -2-pyrrolidone-5-carboxylate (0.4 2.7). g) and heated to 60 ° C. After about 2.4 hours, the mixture was allowed to cool to room temperature. The reaction mixture was then treated with 5N hydrochloric acid (787 mL). The reaction mixture was treated with water (3 mL). Insolubles were collected by filtration, washed with 1: 1 tetrahydrofuran / water (? ML) and tetrahydrofuran (5 mL). The insoluble material was dried overnight at 70 ° C in a vacuum oven to give 3- (2-dibenzofuranone) g.Lutamic acid FABMS. m / z = 330 (M + 1), 331 (MH ₂ O).

1 H NMR: d 8.07 (d, 1H), 7.63-7.53 (2H), 7.46 (t, 1H), 7.32 (t, 1H 7.00 (dd, 1H), 4.91 (s), 3.69 (1H), 3.35-2.14 (m, 2H).

Example 38

3- (5,6,7,8-Tetrahydro-2-di-benzofuranoxy) glutamic acid (32)

3- (5,6,7,8-Letrahydro-2-dibenzofuranoxy) glutamic acid was prepared essentially as described in Examples 5 and 6, except that 2-hydroxy-5,6,7,8-tetrahydro-dibenzofuran-methacetic acid was used. spectrum (FABMS); m / z - 334 (Ma 1), 20? (M + 1-CO ₂ ).

¹ H NMR _: (7.32 U, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 4.79 (1H),

3.64 (1H), 2.65 (2H), 2.51-1.70 (brm, 8H).

Analysis for Ο ^ Η-, οΝΟβ:

H, 5.74; N, 4.20. Found: C, 60.96; H, 5.73; N, 4.16.

Example 39

3- (2-Methyl-5-benzofuranyloxy) glutamic acid (33)

3- (2-Methyl-5-benzofuranyloxy) glutamic acid was prepared essentially as described in Examples 5 and 65, except that 5-hydroxy-2-methylbenzofuran was used (FABMS); m / z - 294 (M + 1), 276 (M + 1-H ₂ O), 249 (M + 1-CO ₂ ).

1 H NMR; d 7.31 (d, 1H), 6.83 (d, 1H), 6.70 (dd, 1H), 6.47 ( _s , 1H), 4.75 (t, 1H), 3 63 (1H), 2.36 (s, 3H), 2.26-2.12 (m, 2H). Analysis For C14Hi:

calculated; C 57.34 H 5.15 N 4.78 found; C 57.45 H 5.10 N 4.64.

Example 40

3- (5-Berisothiophenyloxy) -3-butyric acid (34)

3- (5-Benzothiufenyloxy) glutamic acid was prepared essentially as described in Examples 5 and 6, except that 5-hydroxybenzothiophilia Mass Spectrum (FABMS) was used; m / z = 296 (M + 1), 251 (M + 1-CO ₂ ).

¹ H NMR: d 7.82 (d, 1H), 7.69 (d, 1H), 7.34 (d, 1H), 7.16 (d, 1H), 6.93 (dd, 1H), 4.84 (q, 1 H), 3.65 (1 H), 2.31-2.12 (m, 2 H).

Analysis for C13H13NO5S:

H, 4.44; N, 4.74. Found: C, 51.38; H, 4.34; N, 4.70.

Example 41

3- (4- (4-Chloro-enyl-1-pyridin-2-yl-methyl) -yl) -phenoxy) -glutamic acid (35)

3- (4- (4-Chlorophenylpyridin-2-ylmethyl) phenoxy) glutamic acid was prepared essentially as described in Examples 5 and 6 except that Pyridin-2-yl-4- Hydroxy-4-chlorodiphenylmethane Mass spectrum (FABMS): m / z = 441 (M + 1), 423 (M + 1-H 2 O), 397 (M + 1-CO ₂ ).

1 H NMR: d 6, 48 (1H), 7.70 (1H), 7.35-6.66 4.73 (1H), 3.61 (1H), 2.47 (2H), 2.27- 2.05 (10H); 5.60 (1H); (m, 2H).

Example 42

3- (4-Biphenyl-1,2,4-triazole-3-thio) glutamic acid (36)

3- (4-Benzyl-1,2,4-triazole-3-thio) glutamic acid was prepared essentially as described in Examples 7 and 8, except that 4-bertzyl-1,2,4 was used. -triazole-3-thiol

FABMS: m / z = 337 (M + 1), 319 (M + 1-H ₂ O).

1 H NMR: d 8.68 and 8.66 (1H), 7.32-7.26 (m, 1H), 5.19 and 5.16 (2H), 4.20 and 4.33 (1H), 3.71-3.63 (m, 1H); 2.4-2.0 (m, 2H).

Analysis for C1 ^ H1 & N4Q4S.0,5 H2O:

H, 4.96; N, 16.22. Found: C, 48.88; H, 4.93; N, 16.37.

Example 43

3- (1-Benzyl-1,2,4-triazole-3-thio) glutamic acid (37)

3- (1-Benzyl-1,2,4-triazole-3-thio) glutamic acid was prepared essentially as described in Examples 7 and 6, except that 1-benzyl-1,2,4-triazole was used. -3-thiol- Two dlastereomer mixtures, 37B (A / B 37A (A / B = 2: 1)) were determined by cation exchange chromatography,

Mass spectrum (FABMS): m / z = 337 (M + 1), 319 (M + 1-H ₂ O)

1: 4) a

1 H NMR; d 8.63 and 8.61 (1H), 7.35-7.24 (m, 5H), 4.46 and 4.34 (1H), 3.66-3.57 (1H), 2.4-2.0 (m. Analysis pn.i C τ i:

calculated: C 49.99 H 4.79 N 16.66 S 9.53 Found: C 49.91 H 4.91 N 16.47 S 9.26.

5.33 and 5.31 (2H) (2H)

Example 44 essentially as described in Example 1, 5- (2-chlorophenyl) ether) -1.2m / z = 397 (M + 1), (q, 1H), 7.50-7.23 (m, 4H), 4.30 and 3.63 and 3.61 (3H), 2.19 (m, 1H).

H ₂ 0:

N 12.94 N 12.67.

3- (5 - ((2-chlorophenyl) ether) -1,2,4-triazol-3-thio) glutamic acid (38)

3- (5 - ((2-chlorophenyl) etheriyl) -1,2,4-triazole-3-thl) glutamic acid is prepared 7 and 8 with the exception of eyes that

Of 4-trlazole-3-thiol.

Mass Spectrum (FABMS):

1H NMR: d 8.02 (1H), 7.87 4.13 (1H), 3.75 (m, 1H),

H, 4.89. Found: C, 44.15; H, 4.64.

Example 45

3- (2-Pyrimidirithio) glutamic acid (39)

3- (2-Pyrimidine) glutamic acid was prepared essentially as described in Examples 7 and 8, except that 2-pyrimidine thiol was used. Mass Spectrum (FABMS): m / z = 258 (M + 1).

1 H NMR: d 8.59 and 8.58 (2H), 7.18 (1H), 4.60 (m, 1H), 3.70 and 3.56 (1H), 2.44-2.04 ( bm, 2H).

ř · ·

Example 46

3- (1-Methyltotrazole-5-thio) glutamic acid (40)

3- (1-Methyltetrazole-5-thio) glutamic acid was prepared essentially as described in Examples 7 and 8, except that 1 - methyl etrazo 1 - 5 -1 hioiu was used. Mass spectrum (FABMS) m / z = 262 (M + 1).

1 H NMR: d 4.53 and 4.30 (1H), 3.93 and 3.89 (3H), 3.79 and 3.63 (1H), 2.16 (bm, 2H).

Example 47

Methoxykarboriyl N-2-oxa-3-aza ^_ "bicyclo [2.2.2] oct-5-ene (V)

A suspension of methyl N-hydroxycarbamate (17.81 g) in methyl chloride (350 mL) was cooled to about -13 ° C (ice / acetori bath) and then treated with 1,3-cyclopentane (14, 24 g) and a suspension of tetrabutyl ammonium periodate (64.73 g) in methylene chloride (550 ml). The periodate suspension is added over one hour, causing the reaction temperature to rise to a maximum of -5 ° C.

Once the periodate addition is complete, the reaction is stirred for three hours at room temperature. a temperature of approximately 10 ° C. Add cautiously 10% sodium bisulfite solution (750 mL) while cooling in an ice / acetone bath. After approximately 45 minutes, the sodium bisulfite solution is complete. The organic phase is separated, washed with water (2 x 200 mL) and saturated sodium bicarbonate solution (2 x 500 mL). The organic phase was dried over sodium chloride, filtered and concentrated in vacuo to give 180 g of crude product. A solution of the crude product in methylene chloride was added to silica gel (200 g) and the resulting mixture was evaporated to dryness. The title compound was isolated by flash silica, eluting with hexane / ethyl acetate (5: 1, 1L) and hexane / ethyl acetate (7: 3, 500 mL). Fractions containing the desired compound were combined, dried with brine and magnesium sulfate and zkoricentru it in vacuo to obtain 27.65 N cj met.ho xyk.arbony ~ 1-2 ~ ^_ oxa-3-aza-bicyclo [2.2.2 ] oct-5-enene as an oil76

The oil was placed in a freezer to induce crystallization. Mass spectrum (FDMS): m / z = 169.

N, 8.28. Found: C, 56.66; H, 4.54; N, 8.43.

Example 46

N-methoxycarbonyl-3,6-dicarboxy-1-oxa-2-azacyclohexane (VI)

A solution of the compound of Example 47 (1.7 g) in toluene (26 ml) was treated with a 0.1 M solution of tetrabutylammonium hydrogen sulphate (0.23 g) in water (7 ml). This biphasic mixture is cooled to approximately -10 ° C (ice / acetate bath) and treated with a 0.2 M potassium permanganate solution (2.76 g potassium permanganate in 90 ml of water). hours and 20 minutes. The resulting suspension was mechanically stirred for two hours. The reaction mixture was filtered and the insoluble product was washed with ethyl acetate and water. The pH of the filtrate was adjusted to between about 8.24 and about 8.2. 2.01 1N hydrochloric acid The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were dried over sodium chloride and magnesium sulfate, filtered and concentrated in vacuo to give 245 mg of N-methoxycarboriyl-3,6-dicarboxy-1-oxa-2-azacyclohexane as a white powder.

Mass spectrum (FDMS): m / z = 234 (M + 1), 203 (M + 1-OCH ₃ ), 144 (M + 1 -2 CO ₂ ).

1 H NMR. d 4.72 (1H), 4.27 (dd, 1H), 3.64 ( _a , 3H), 2.16 (1H), 1.85 (2H), 1.52 (1H).

Example 49

Methyl 1-3- (1,2,4-triazol-1-yl) -4-pyrrolidone-5-carboxylate (IX)

A mixture of Example 4 (318 mg), triphenylphosphine (577 mg) and 1,2,4-triazole (152 mg) in dry tetrahydrofuran (4.5 mL) was cooled to about 5 ° C and treated with a solution of dicthylazodicarboxy acetate (383 mg) in ten minutes. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After about 17 hours, the solution was concentrated in vacuo and allowed to stand at room temperature under reduced pressure to give a crystalline solid. This solid was. Dilute with chloroform and purify by thin layer centrifugation chromatography eluting with ethyl acetate / hexane (1: 1) followed by ethyl acetate / hexane (3: 1), ethyl acetate, ethyl acetate / methanol (19: 1) and acetate / hexane systems. methanol (9: 1).

The fractions containing the desired compound were combined and concentrated in vacuo to give 280 mg of methyl 3- (1,2,4-triazol-1-yl) -2-pyrrolidone-5-carboxylate Mass spectrum (FOMS); m / z = 211 (M + 1) ¹ H NMR: d 8.72 (1H), 8.56 (1H), 7.96 (1H), 5.27 (1H), 4.35 (1H), 2.90 (m, 1H); 2.43 (1H).

Analysis for C3H10N4G3:

H, 4.80; N, 26.66. Found: C, 46.02; H, 4.71; N, 12.94.

Example 50

3- (1,2,4-Triazol-1-yl) glutamic acid (41)

The compound of Example 49 (420 mg) was treated with 5N hydrochloric acid (10 mL) and the resulting mixture was heated to reflux. After 32 hours, the mixture was evaporated to dryness. The residue was diluted with acetone (20 mL) and sonicated in an ultrasonic bath and filtered. The solid product was dried. This product is dissolved in water (3 IU) and in tetrahydrofuran (0.2 ml) and purified by cation exchange chromatography. (AG5OW-X8) eluting with water and then tetrahydrofuran / water (1: 1) and 10% Pyridine. The fractions containing the desired compound were combined and evaporated to dryness. The residue was diluted with water (100 mL) and evaporated again to dryness. This process was repeated three times. The residue is dried under reduced pressure to give a white glass. This glass is treated with acetone and the resulting mixture

The filter is filtered. The solid material was dried under vacuum to yield

405 mg of 3- (1,2,4-trluzol-1-yl) glutamic acid -

Mass spectrum (FABMS) m / z 215 (M + 1) , 197 (M + 1-H ₂ ) 1K NMR: : d 8.50 a 8.46 (1H), 7.91 _and 7, 89 OH), 5.38 and 5.26 (1H) 4.21, 3 _; , 68 and 3.23 (1H). 2.90-2., 24 (2H) Example 51

Methyl 3- (tetrazol-1-yl) -2-pyrrolidone-5-carboxylate and methyl 3- (tetrazol-2-yl) -2-pyrrolidone-5-carboxylate (IX)

A mixture of the compound prepared according to Example 4 (318 mg), triphenylphosphine (577 mg) and tetrazole (155 mg) in dry tetrahydrofurart (4.5 ml) was cooled in an ice / water bath and treated with a solution of diethyl azodicarboxylate (383 mg) in After the addition was complete, the reaction mixture was allowed to warm to room temperature. After about 17.5 hours, the solution was concentrated in vacuo. The solid was diluted with chloroform (10 mL) and concentrated in vacuo. repeat to remove traces of tetrahydrofuran- The residue was dissolved in chloroform (10 mL), purified by thin layer centrifugal chromatography eluting with ethyl acetate / hexane (1 of 1) followed by ethyl acetate / hexane (9: 1), ethyl acetate, ethyl acetate methanol (9: 1) and ethyl acetate / methanol (4: 1). The first eluting isomer is a tetrazol-2-yl compound and the second eluting isomer is a tetrazol-1-yl compound. Fractions containing each of these isomers in pure state are collected and concentrated in vacuo. The residue is triturated in methylene chloride (3 mL). and the desired compounds were isolated by filtration to give 46 mg of methyl 3- (tetrazol-2-yl) -2-pyrrolidone-5-carboxylate and 227 mg of methyl 3- (tetrazol-1-yl) -2- pyrrolidone-5-carboxylateMethyl 3- (tetrazol-1-yl) -2-pyrrolidone-5-carboxylate

Mass spectrum (FDM.S): m / z ~ 212 (M-1)

1 H NMR: d 9.51 ( _S , 1H), 8.96 (s, 1H), 5.62 (t, 1H), 4.34 (t, 1H),

3.70 ( _s , 1H), 3.07 and 2.50 (m, 2H).

Analysis for C7H9N5O3:

calculated: C 39.81 H 4.30 N 33.16 Found: C 40.06 H 4.25 N 33.42.

Methyl 3- (tetrahydro-2-yl) -2-pyrrole to n-5-carboxylate

Mass Spectrum (FOMS): m / z - 212 (M + 1);

1 H NMR: d 9.02 (s, 1H), 9.00 ( _S , 1H), 5.94 (t, 1H), 4.39

3.71 (s> 1H), 3.10 and 2.52 (m, 2H).

Analysis for C7H9N5O2:

calculated: C 39.81 H 4.30 N 33.16 found: C 40.02 H 4.32 N 32.88,

Example 52

3- (terazol-2-yl) glutamic acid (42)

3- (terazol-2-yl) glutamic acid was prepared essentially according to the procedure of Example 50 from methyl 3- (tetrazol-2-yl) -2-pyrrolidin-5-carboxylate (7 mg)

1 H NMR: d 8.88 and 8.87 (1H), 6.70 (m, 1H), 3.94 and 3.65 (1H), 2.80

2.64 (m, 1H); 2.48-2.36 (m, 1H).

Example 53

3- (terazol-1-yl) glutamic acid (43)

3- (terazol-2-yl) glutamic acid was prepared essentially as described in Example 52. from methyl-3- (tetrazol-1-yl) -2-pyrrolidin-5-carboxylic acid ¹ H NMR. (de-OMSO / d-TFA): 9.50, 9.48, 8.43 (m), 5.48 (m), 4.13 (m), 3.78 (m), 3.17 (m) m), 2.89-2.65 (m), 2.24 (m).

Example 54 (25.2R) -N- (tert -Butoxycarbonyl) -4- (tert-butoxycarbonyloxy) proline methyl ester (XV)

A solution of 4-hydroxy-1'-proline methyl ester hydrochloride (1g), triethylamine (2.5 ml) and N, N-dlmothylamine rinopyridine (134 mg) in methylene chloride (50 ml) was treated with di-tert-butyldicarboxylate (2.8 mL). After 18 hours at room temperature the solvent was evaporated. The organic phase was dried, magnesium sulphate and evaporated to dryness. The title compound was purified by flash chromatography eluting with hexane / ethyl acetate (10L). thereby obtaining 1.6 g of (25.2R) -N- (tert-butoxycarbonyl) -4- (tert-butoxycarbonyloxy) prolinomethyl] ester [a]_D = -29.7 (c = 1, CHCl3)₃1 H NMR. (200MHz, COCl₃d: 5.15 (m, 1H), 4.40 (m, 1H), 3.74 (s, 3H), 3.90-3.50 (m, 2H), 2.60-2.10 ( m, 1 H, 1.53, 1.50, 1.45 and 1.41 (4_WITH, 18H).

Example 55

Methyl (3R, 5S) -N- (tert-butoxycarbonyl) -3- (tert-butoxycarbonyioxy) -2-pyrrolidori-5-carboxylate (XVI)

A mixture of ruthenium dioxide hydrate (60 ml and 10% aqueous sodium periodate (30 ml)) was treated with a solution of the compound prepared according to Example 54 (Ig) in ethyl acetate (10 ml) and stirred vigorously at room temperature. The combined organic solutions were treated with isopropyl alcohol to quench the residual ruthenium oxidant. The resulting mixture was filtered through Celite. 906 mg of methyl (3R, 55) -N (tert-butoxycarbonyl) -3- (tert-butoxycarbonyloxy) -2-pyrrolidine-5-carboxylate [a] _D = +15, 1 ( _c = 1. CHCl 3).

1 H NMR (200 MHz, COCl 3): d 5.31 (dd, 1H), 4.41 (dd, 1H), 3.80 (s,

3H), 2.70 2.25 (m, 2H), 1.50, (s, 9H).

Example 56

Methyl (3R, 5S) -3-hydroxy-2-pyrrolidone-5-carboxylate (XVI I)

A solution of the compound prepared by the method of Example 55 < 1.5

g) in methylene chloride (80 ml) was treated with trifluoroacetic acid (3.3 ml). After two hours at room temperature, the solvent was dissolved. The remainder is three or three. b) to give 536 g of methyl (3R, 5S) -3-hydroxy-2-pyrrolidinone-5-carboxylate as a white solid, m.p. 99 DEG-100 DEG C., eluting with ethyl acetate. .

[α] _D - + -38.0 (c = 0.5, M @ 0 H),

1 H NMR (200 MHz, D ₂ O): d 4.24 (m, 2H), 3.50 (s, 3H), 2.44 (m, 1H) 2.10, (m, 1H).

Example 5?

Methyl (R, 5S) -3- (4-methylphenoxy) -2-pyrrole-5-carboxylate (XVIII.)

A mixture of the compound prepared according to the method of Example 56 (477 mg), triphenylphosphine (865 ml) and p-cresol (357 mg) in tetrahydrofuran (5 ml) was cooled to 0 ° C and treated with diethyl azodicarboxylate (520 ml). . After about 18 hours at room temperature, the mixture was evaporated to dryness. The residue _was purified by flash silica gel chromatography eluting with hexane / ethyl acetate (3: 1) to give methyl- (3R, 5S) -3-. (4-methylphenoxy) -2-pyrrolidine-5-carboxylate contaminated with tri-1. phenylphosphine ox.

1 H NMR. (200 MHz, CO ₃ ): d 7.16-6.80 (4H), 6.18 (bs, 1H), 4.63 (t, 1H), 4.24 (t, 1H), 3.60 (s, 3H), 3.10-2.90 (m, 1H), 2.45-2.20 (m, 1H), 2.29 ( _s , 3H).

Example 58

(2S, 4 $) - 3- (4-Methylphenoxy) glutamic acid (44)

A mixture of the compound of Example 57 and 6N hydrochloric acid was heated to reflux and heated to reflux. After approximately 18 hours, the mixture was evaporated to dryness. (? S, 4S) -3- (4-Methylferioxy) glutamic acid was purified by cation exchange chromate (DOWEX 50X6-100) eluting with 10% pyridine / water. Melting point 177.8 ° C (dec.).

[α] C -38.0 (r = 1, 10λ pyridine / water) · iw hiwp (200 MHz, CO 300 + KOD): d 7.04-6.83 (d) (dd) 1 H, 2.36-2.27 (m, 1 H), 2.21 (5, 3H), 2

EXAMPLE 7 5 59 _J (dd, 1H) .3,48, 03-1,96 (m, 1H).

(2S, 4S) -3- (2-Riaphthyloxy) glutamic acid (45)

(2S, 4S) -3- (2-Riaphthyloxy) glutamic acid was prepared essentially as described in Examples 57 and 58, except that 2-naphthol was used.

Melting point 176-177 ° C (decomposition).

⁼ —14.0 (r · = 1, 10% pyridine / water a)

1 H NMR (200 MHz, D ₂ O + CO 3 100 + KOD): d 7.74-7.65 (m, 3H, 7.40-7.18 (m, 4H), 4.73 (dd, 1H) 3.54 (dd, 1 H), 2.47-2.38 (m, 1 H),

2.11-2.04 (m, IH).

Example 60

(2S, 4S) -3- (4-Phenylphenoxy) glutamic acid (46)

(2S, 4S) -3- (4-Phenylphenoxy) glutamic acid was prepared essentially as described in Examples 57 and 58, except that 4-phenylphenol [α] D = -5.8 (c 1, 10 % Pyridirium / water), ¹ H NMR (200 MHz, CD ₃ OD + CO): d 7.57-6.99 (m, 9H), 4.64 (dd, 1H), 3.49 (dd, 1H) 2.5-2.3 (m, 1H), 2.1-1.9 (m, 1H).

Example 61

1 /, ....

(47)

(2S, 4S) -3- (2-Dibenzofuranoxy) glutamic acid was prepared essentially as described in Examples 57 and 58, except that 2-hydroxydibenzofuran was used.

Cultt -32.0 (c = 0.5, 10% pyridine / water).

¹ H NMR (200 MHz, CD 3 OD + KOO): d 7.94 (d, 1H), 7.54-7.42 (m, 4H),

7.3 (td, 1H), 7.13 (dd, 1H), 4.68 (dd, 1H), 3.56 (dd, 1H), 2.522.38 (m, 1H), 2.11-1 95 (m, 1 H).

Example 62

3- (4- (4-Feriylethenyl) phenoxy) glutamic acid (48)

3- (4- (4-Phenyl-ethenyl) phenoxy) glutamic acid is prepared essentially as described in Examples 5 and 6, except that trans -4-hydroxystilbene is used.

1 H NMR: d 7.50 (m, 4H), 7.32 (t, 2H), 7 7.17 (m, 1H), 7.04 (d, 2H), 6.77 (d, 2H), 4.79 (t, 1 H), 3.62 (m, 1 H), 2.19 (m, 2 H). Analysis for C19H15NO5:

calculated: C 66.85 H 5.61 N 4.10 found: C 66.63 H 5.48 N 3.87.

Example 63 1

3- (4- (2-Feriylethenyl) phenoxy) glutamic acid (49)

3- (4- (2-Feriylethenyl) phenoxy) glutamic acid was prepared essentially according to the method of Examples 5 and 6, except that it was prepared. Use 2-phenylethyl phenol Mass Spectrum (FOMS): m / z 344 (M + 1)

1 H NMR (OMF?): D 6.91-6.84 (m, 4H), 6.78 (m, 3H), 6.39 (d, 2 Η),

4.54 (t, 1H), 3.66 (t, 1H), 2.45-2.38 (m, 4H), 2.07 (t, 2H).

Analyzing for C-IgH2NNOs:

calculated: C 66.46 H 6.16 N 4.08 found: C 66.19 H 6.20 N 3.97.

Example 64

3- (4- (3-Phenyl-propyl-phenoxy) -glutamic acid (50) (i) A mixture of diberisoylmethane (100 g) and 5% P and 11 a d a h a

(10.0 g) in ethyl acetate (600 ml) and concentrated sulfuric acid (15 ml) are hydrogenated at 50 psi hydrogen at room temperature. After two hours the reaction mixture is allowed to cool to room temperature. The reaction mixture is filtered through talc. . The filtrate was treated with water (2 x 250 mL) and the phases were separated. The organic phase was collected by tosylation, and the mixture was filtered. k ». * · · 'kk. ^ - 4 kzr.nr.ru Ί>' r ^x ? 4: j ri t <r

I 'y U. t I IM *' 1. J.t. (250 ml). The organic phase is dried over sodium chloride, then with magnesium sulphate, and the residue is concentrated to a volume of 5.34 g of 1,3-diphenylproparium (ii) Solution 1,3 - diphenyropropane (75.34 g) and acetic anhydride (39.18 g) in 1,1,2,2-tetrachloroetharium (285 ml) was cooled to approximately 35 ° C in an acetone / dry ice bath. After the addition of aluminum chloride (about 60 minutes), the resulting reaction slurry was allowed to warm to room temperature. After about 4.6 hours at room temperature, the reaction mixture was cooled to about 0 ° C in a water / ice bath and The reaction mixture was treated with water (380 ml) and the phases were separated. The aqueous layer was treated with chloroform (3 x 200 ml) and the phases were separated. The combined organic phases were washed with water (200 ml). ml), dried over sodium chloride, filtered and quenched they are filtered under vacuum to obtain an oil. The oil is distilled under vacuum. Distillation at 204 to 213 ° C under pressure (0.07998 kPa) yields 39.07 g of 4 '- (3-phenylpropyl) acetophenone as an oil ( iii) A suspension of 4 '- (3-phenylpropyl) acetophenone (39.07 g) and chloroperoxybenzoic acid (124.48 g) in methylene chloride (400 mL) was heated to reflux. (Note: m-chloroperoxybenzoic acid used in this reaction is a 1: 1 mixture of m-chloroperoxybenzoic acid and m-chlorobenzzoic acid) - After 23.5 hours, the reaction mixture is allowed to cool to room temperature. The reaction mixture was filtered and the insoluble material was washed with methylene chloride (100 mL). Water (500 mL) was added to the filtrate. The pH of the biphasic solution is adjusted

The organic phase was treated with a 10% aqueous potassium carbonate solution (3 x 500 ml) and then with brine (2 x 500 ml). The organic phase was dried over sodium chloride, then magnesium sulfate, filtered and concentrated in vacuo to give a solid. 43.4 g of 4- (3-phenyl-propyl) -phenylacetate are obtained (iv) To a mixture of 4- (3-phenylpropyl) -phenylacetate in methanol *

(610 mL) and water (530 mL) were added sodium carbonate (72.37 g). The resulting suspension is refluxed. After 2.7 hours, the reaction mixture was allowed to cool to room temperature. After 15 minutes, the reaction mixture was treated with concentrated hydrochloric acid (117 mL) for 15 minutes. The reaction mixture was then concentrated in vacuo.

The reaction mixture was treated with diethyl ether (750 mL) and the phases separated. The aqueous phase was treated with diethyl ether (3 x 500 mL). The combined organic phases were dried over sodium chloride, then magnesium sulfate, filtered and concentrated in vacuo to give an oil. The oil was dissolved in acetone and treated with silica gel; 230 a? 400 mesh (76-38 µm mesh) (76 g) and the resulting mixture was evaporated to dryness. The title compound was isolated by flash silica gel.

(chroma t.ogr < dfií z and eluting the sy ethanol (96.5: 2.5 : Η 8 x 250 ml) acetate / methanol (94 : 5: 1,4 χ 250 Iate / methanol (89: : 10: 1,) - Fractions

250 ml) and finally hexane / ethylation of Frakee containing 4- (3-propylphenyl) phenol were combined and concentrated in vacuo to give an oil at room temperature, the oil was 1 system (v). prepared according to the method of Example 4 (0.5349 g), triphenylphosphine (1.00 g), and 4- (3-propylphenyl) phenol (0.8100 g) in letrahydrofuran (4.7 ml) were cooled to approximately 1 '. The reaction mixture was treated with a solution of diethyl azodicarboxylate (0.6645 g) in letrahydrofuran (10 mL). After completion of the addition, it is left to react. After approximately <8.5 hours, the resulting brown solution was concentrated in vacuo. The residue was diluted with chloroform (2 mL), insoluble.

The oil was dissolved in methylene chloride and purified, with preparative thin layer centrifugal chromatography (4 mra plate, flow rate 8 ml / min) eluting with 50% hexane / ethyl acetate after elution. The first fraction, then 100% ethyl acetate-fraction containing n, w / w. /, «, ···. i, / ·. - i, ·. ? . Λ. /) z- '.Kl] -j • ..................... cú-U J .. -'n-. j * _yu-B uo.j.> * -> j. i Uhl 'sulfate, filtered and zkonceritrují under vacuum, thus obtaining 0.916 g ka methyl] .- 3- (4- (3-phenylpropyl) ferioxy 2-pyrrolidone-5-carboxylate as a white solid.

(vi) A mixture of lithium hydroxide ¢ 0.0464 g) in water (0.5 ml) and tetrahydrofuran (1.2 ml) was treated with methyl-3- (4- (3-phenylpropyl) ferioxy] -2-pyrrolidinediamine 5-carboxylate (0.2263 g) and heated to 60 ° C. After about 4.75 hours, the reaction was allowed to cool to room temperature. After about one hour, the mixture was allowed to cool to room temperature. The reaction mixture was then concentrated in vacuo to give a solid. The solid was collected by filtration to give the title compound as a white solid (347 mL). The solid was triturated in toluene (10 mL) and water (10 mL), and insoluble materials were collected by filtration to give 3- (4- (3-phenylpropyl) phenoxy) -2-pyrrolidone-5-carboxylic acid.

1 H NMR: d 8.43 (1H), 7.24 (2K), 7.16-7.05 (m, 5H), 6.86 (2H), 4.62 (t, 1H), 4.07 (t, 1H), 2.67 (m, 1H), 2.53 (4H), 1.86-1.75 (m, 3H).

(vil) A mixture of lithium hydroxide (0.0305 g) in water (0.3 ml) and tetrahydrofuran (1.1 ml) was treated with 3- (4- (3-phenylpropyl) ferioxy] -2-pyrrolidori-5-carboxylic acid (0.1442 g) and heated to 60 ° C. After about 6.0 hours, the reaction was allowed to cool to room temperature. After about 1 hour at room temperature, the reaction was treated with 5N hydrochloric acid (255 ° C). Insolubles were separated by tetrahydrofuran / water (10 ml), then tetrahydrofuran (5 ml) and finally water (5 ml) and the resulting 3- (4- (3-phenylpropylphenoxy) glutamic acid) was dried under vacuum at 60 ° C. C overnight ¹ H NMR (? MMF?): D 6.91-6.71 (m,

3.65 (t, 1H); 2.38-2.02 (ni, 6H);

7H), 6.39 (d, 1.52-1.42 (m,

2K), 4.54 (t, 1H), 2H) Analysis for C 20 OH 23 NO 5 -.

calculated: C 67.21 H 6.49 found - C 66.98 H 6.37

N 3.9 2 N 3.76.

Example 65

3- (4- (4-Phenylbutyl) erioxy) glutamic acid (51) (i) A mixture of 1,4-dibenzoylethene (20 g) and 5% palladium carbonate (2.0 g) in ethyl acetate (375 mL) , ethanol 375 (ml) and concentrated sulfuric acid (5 ml) were hydrogenated at. at 50 DEG C. After two hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated from talc. The filtrate was concentrated in vacuo. The material was water (250 mL) to form crystals, and the crystals were collected by filtration to give 1,6-diphenylbutyl (17.75 g).

Mass spectrum (FOMS): m / z 210 was filtered through and treated with ProSmixture

1 H NMR: d 7.24 (4H), 7.13 (6H), 2.56 (4H), 1.55 (4H). For C 18 H 18: calculated; C 91.37 H 8.63 found; C 91.39 H 8.61.

(ii) A solution of 1,6-dl ferrobutyrate (15.42 g) and acetic anhydride (7.49 g) in 1,1,2,2-tetrachloroethane (54 mL) was cooled to about -20 ° C. in an acetori / dry ice bath. Aluminum chloride (19.55 g) was added to the solution at such a rate that the temperature was kept below -20 ° C. After the addition of aluminum chloride was complete (about 40 minutes), the resulting reaction slurry was allowed to warm. room temperature. After about 2.75 hours at room temperature, the reaction mixture was cooled to about 0 ° C in a water / ice bath and then treated with 6N hydrochloric acid (22 mL) for 20 minutes. the phases are separated. The aqueous layer was treated with chloroform (3 x 50 mL) and washed with brine (50 mL), filtered, and concentrated in vacuo. Vacuum · Dissolve the product in diethyl ether. It is then treated with silica gel U.S. Pat. 230-400 mesh (42 mesh) (42 g) the resulting mixture was evaporated to dryness. The product was subjected to flash silica filtration, eluting with hexane / ethyl acetate (4: 1, 10 x 250 mL). The fractions containing the desired product were corrected in vacuo to an oil. The distillation at 197 to 210 0 / 0.03999 kPa resulted in 7.70 g of 4 '- (4-ferriyl butane) acetophenone as an oil. Tactile Spectrum (FOMS): m / of 252

1 H NMR: d 7.84 (H _: 2H), 7.31-7.20 (4H), 7.13 (3H)

2.56 (t, 2H), 2.51 ( _s , 3H), 1.55 (4H).

(Iii) Susperise 4- (3-phenylbutyl) acetophenone (7.63 g) and perchlorbenzoic acid acetic acid (22.95 g in methylene chloride (75 mL)) were refluxed (-). Note: The m-chloroperoxybenzoic acid used in this reaction is a 1: 1 mixture of m-chloroperoxyberizoic acid and m-chlorobenzzoic acid) - After 25.25 hours the reaction mixture is allowed to cool to room temperature.

2.3 hours at room temperature, the reaction mixture was filtered and the insoluble material was washed with methylene chloride (50 ml). Water (100 mL) was added to the filtrate. The pH of the biphasic solution was adjusted from 2.77 to 10.18 with 5N sodium hydroxide solution (12 ml) and the phases were separated. The organic phase was treated with 10% aqueous potassium carbonate solution (3 x 50 ml) and then with brine (3 x 100 ml). ml). The organic phase was dried over sodium chloride then magnesium sulfate, filtered and concentrated in vacuo to give 8.31 g of 4 '(4-phenylbutyl) phenylacetate Mass Spec (FOMS): m / z 268

1 H NMR: d 7.2.6-7.14 (7H), 6.68 (2H), 2.57 (4H), 2.21 (s, 3H), 1.56 (4H).

(iv) To a mixture of 4- (4-phenylbutyl) phenylacetate (8.29 g) in methanol (112 ml) and water (97 ml) was added sodium carbonate (13.10).

89 g) - The reaction mixture is refluxed. After 3.5 hours, the reaction mixture was allowed to cool to room temperature. After 25 minutes at room temperature, the reaction mixture was treated with 5N hydrochloric acid (50 mL). Then, the reaction mixture was stirred under vacuum to remove most of the methanol contained therein. The residue was added with diethyl ether (250 mL) and the reaction mixture was treated with 1N hydrochloric acid (3,100 mL) and the phases were separated. in diethyl ether. Then the desired compound was isolated by flash silica gel eluting with hexane / ethyl acetate (20: 1, 92 x 13 mL). The fractions containing the title compound were combined and concentrated in vacuo to give 1.57 g of 4- (4-phenyl-butyl) -phenol as an oil. d 9.06 (s, 1H interchangeable), 7.23 (2H), 7.12 (3H), 6.91 (2H), 61 (2H), 2.55 (2H), 2.45 (2H) 1.57-1.45 (4H).

(v) (0.434 g)

A mixture of the compound Prepared triphenylphosphine (0.8113 g) by the method of Example 4 and 4- (4-phenylbutyl) phenol (0.700 g) in tetrahydrofuran (3.6 ml) was cooled to about 1-2 ° C and Treat with diethyl azodicarboxylate (0.5386 g) for 2 minutes. After completion of the addition, it is left to react. warm the suspension to room temperature. After about 23 hours, the solution was concentrated in vacuo. The residue was diluted with chloroform (1 mL), the insoluble matter was removed by filtration, and the filtrate was concentrated in vacuo. The residual oil was dissolved in methyl chloride (4 mL) and purified by PreParative centrifugation chromatography in thin layer, (4 mm plate, flow rate 8 ml / min), eluting with 50% hexane / ethyl acetate While eluting the first lane, then 100Ϊ-ethyl acetate. The fractions containing the desired compound were combined and concentrated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give mothyl-3- (4- (4-phenylbutyl) phenoxy) -2-pyrrolidone-5-iodide. , ar boxy.lát (583 mg) ..

¹ H NMR d 6, 23 (2H), 7.13 (3H), 7.04 (2H), 6.85 (d, 2H), 4.83 (t, 1H), 4.21 (t, 1H) ), 3.65 (s, 3H), 2.93-2.83 (m, 1H), 2.54 (m,

4K), 1.89 (m, 1H), 1.53 (4H).

(vi) A mixture of lithium hydroxide (0.072 g) in water (0.9 ml) and 1 liter of tetrahydrofuran (2.9 ml) was worked up. methyl (4 (4-phenyl-phenyl) -phenoxy) -2-pyrrolidine-5-carboxyxylate (0.370 g) and heating at room temperature. 60 * C. After about 4.0 hours, the reaction mixture was allowed to cool to room temperature. After approximately 2.25 hours at room temperature, the reaction mixture was treated with 5N hydrochloric acid (604 mL). The resulting biphasic solution was kept at 5 ° C for 18 hours with cooling. The biphasic solution was treated with water (2 mL). The resulting milky solution with sonication resulted in crystal formation. The crystals were collected by filtration, washed with 1: 1 tetrahydrofuran / water (10 mL), tetrahydrofuran (10 mL) and water (10 mL). Crystals. then dried overnight in a vacuum oven at 60 ° C to give 3- (4- (4-phenylbutyl) phenoxy) glutamic acid (106 mg).

FABMS: m / z 371 (m + +1) @ + (M +);

2.57-2.51

17 * 5 H 7 07 / J

W woven Mf3. J

4.71 (1H), 3.62 (1H),

1.56-1.50 (m, 4H).

Analysis for C21H25NO5:

H, 6.78; N, 3.77. Found: C, 68.20; H, 6.93; N, 3.65.

6.66 (m, 3H); 2.26-2.06 (m, 3H);

Industrial use. The glutamic acid derivative affects excitatory amino acid receptors and is therefore useful in the treatment of neurological disorders.

Claims (8)

PATENTOVÉ Claims (/ 5 O < A glutamic acid derivative of the general formula I H ₂ N W, Cl) where is Z is NR ^5, oxygen or sulfur, In the group -CH <3 -p. -CCH ₂₎ q-, -CCH ₂₎ q _T3 -p>. -CCH ₂₎ qC0-, -CCH ₂ ) _q O-, -CCH ₂ ) q CH = CHCCH 2) q -. - (CH3) qCH = CH. -CHCHCO-. -CHCHCOR ⁶ , -CCH 2 or CHOHR ⁶ . -CCH2) qCHOH, -CCH _{2 is} qOR ⁶ , - OCCH ₂ ) _q -, NR ⁵ , SO, SO 2 oxygen or sulfur, n 0 or 1, m 0 or 1, ρ 0,1,2 or 3, 0 to 6 1 or 20 or 1, provided that the sum of n, m, p and s is at least 1, R ¹ and R ² independently of each other an aryl group, a substituted aryl group, a heterocyclic group or a substituted heterocyclic group. R ³ a hydrogen atom or a group , protecting k ar boxyl group. Fď a hydrogen atom or a group , protecting carboxyl group. R ⁵ hydrogen, alkyl group with 1 to 10 carbon atoms acyl or SO 2 (C 1-4 alkyl), R ^{6 represents a} C 1 -C 10 alkyl group, provided that when n is 0 and 1, R ¹ represents a group selected from the group consisting of tetrazolyl, triazolyl, pyrimidazolyl, pyrimidinyl, pteridinyl. 1,2,4-triazine-3,5-dionyl, pyrazolonyl. 7H-purinyl. xanthinyl, 3-ethyl-5-hydroxy-1,2,4-thiadiazolyl, 3-hydroxy-1,2,4t-hia (1-aminodaninyl, hydaritolnyl and Pseudotyl), and other conditions, that when n is 1, m 1 and W is NR 5, SO, SO ₂ , oxygen or sulfur, it is s 1, and that when n is 0 and s is 0, m and W is a group of the formula - (CH ₂ ) q CO-, - (CH ₂ ) _q Q -, -CH = CHCO-, -CH = CHCOR 6, - (CH ₂ ) _q CHOHR 6, - (CH ₂ ) _q CHOH, - (CH ₂ ) q COR 6, -O (CH ₂ ) _q -, NRS, SO, SO _2, an oxygen or nitrogen atom, or a pharmaceutically acceptable salt thereof. 2- Glutamic acid derivative according to claim 1 of the general formula And who means 2 is NR5, oxygen or sulfur; W is -CH (3-p), - (CH ₂ ) _q -, - (CH ₂ ) _q CH <3 _-p >, - (CH ₂ ) _q CO-, - (CH ₂ ) _q CH = CH (CH ₂ ) _q -, - (CH ₂ ) _q CH = CH-, -CH-CHCO-, -CH = CHCOR 6, - (CH ₂ ) _q CHCQR 6, - (CH ₂ ) _q COR &, -0 (CH ₂ ) _q -, NRS, SO, SO ₂ , oxygen or sulfur, n 0 or 1, m 0 or 1, P 0,1,2 or 3, q 0 to 6 r 1 or 2 with 0 or 1, ^R1 and R2 are _{independently} aryl, substituted aryl, heterocyclic or substituted heterocyclic group. R3 is a hydrogen atom or a carboxyl protecting group, R4 is a hydrogen atom or a carboxyl protecting group, R ⁵ is hydrogen, an alkyl radical having 1 to 10 carbon atoms, aryl, OR ₂ S0 (one alkyl) group having 1 to 4 - knapsacks atoms, R ^{6 is a} C 1 -C 10 alkyl group, provided that when R ^{1 is} O ¹ , R ^{1 is a} radical of C 1 -C 10 alkyl; A pin selected from the group consisting of tetrazolyl, triazolyl, Pyridazinyl, Pyrimididyl, Pteridyl, 1,2,4-triazirt-3,5-diorilyl, pyrazolonyl, 7H-purinyl, xarithiyl, 3-ethyl-5- hydroxy-1,2,4-thiadiazolyl, 3-hydroxy-1,2,4thladiazolyl, rhodanilnyl, hydantolnyl rly and pseudothiohydantiryl, and with the proviso that when n is 1, m 1 and W is 0 ( CH ₂ ) _q -, NRS, SO, SO ₂ , an oxygen atom or a sulfur atom, denotes s 1, or a pharmaceutically acceptable salt thereof 3. The glutamic acid derivative according to claim 1 'or 2, wherein Z is an oxygen or sulfur atom, W - (CH ₂ ) _q CH = CH-, - (CH ₂ ) _q -, - (CH ₂ ) _q O-, - (CH ₂ ) _q CH = CH (CH ₂ ) _q -, -O (CH ₂ ) _q - and n, with 1, p 0 or 1 and q 0 to 6. A glutamic acid derivative according to claims 1 to 3 in general formulas I where OF oxygen atom, R1 aryl or substituted aryl, R2 phenyl or substituted phenyl, R3 hydrogen atom, R4 hydrogen atom, q 1 to 6 and other symbols have. or a pharmaceutically acceptable salt thereof. - A glutamic acid derivative according to claim 1 wherein Z is oxygen or sulfur; W - (CH ₂ ) _q CH = CH-, ~ (CH ₂ ) _q -, - (CH ₂ ) _q O -, - (CH ₂ ) _q CH * CH (CH ₂ ) _q -, -O (CH ₂ ) _q - a ) n 0, s 1, m 0 , P 0 a R ¹ is tet raznlyjovou nnbn t. r i a z o! y] or v ou, r i F-b i j and) n 1> s 1, m 0 P 0 and R ¹ gr upinu fe riy 1 ovnu v i o b o to f t y 1 o v <11 .ι, which is unsubst i t uovyná neb o subsil l it | 1 S: i 11 '' i '·. dVtp- e-substi tivnts v i „i lenou s file ; a ahr i n., i j at.om h.-fln- O> l il ..! , hydiOXys> ·· up .mu, cyano skuPlnu. ni. t r osk uPiriu, and! kylnvnu a group with ¹ ; 6 carbon atoms alkyl i uPin with 7 to 10 about tomy carbon, cy í 1 o <.i .1 k y 1 o vou group se 3., '· 6 carbon atoms, a.lkoxy group s 1 it has 4 atoms uh 1 i.ku, k ar boxes s k u P inu, s k u i lip acety. The methyl, hydroxymethyl, hydroxymethyl, amino, amino, mercury, and methylfluoromethyl groups, or the disulfide of two adjacent and quarrying carbon atoms with an alkylene group, may be C 3 -C 10 alkylene, C 2 -C 10 alkyloxy, C 1 -C 10 alkylene, C 5 -C 6 cycloalkylene or C 5 -C 6 cycloalkyleneoxy; 6 carbon atoms, or a lower carbon group of the two aryl atoms of the aryl ring to which they are attached, form a ring or pyrimidine or 1-methylthio-5-yl group, or III, with 1, m 0 or 1, p 1 or 2 and R ¹ is phenyl or three. azyl and catheter independently of each other a pyrimidyl or phenyl group which is unsubstituted or substituted by one or two substituents selected from the group. including a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group having 1 and 2? C 7-C alky alky alkyl, C alky-C alky alky alkyloxy, C ry-C ry rycycloalkyl, C 4 alko-C alko alko alkoxy, carboxy, acetyl; carboxymethyl, hydroxymethyl, amino, -1-p-aminomethyl and trifluoromethyl; and Q θ to 6 r 1 n R3 and R4 are each hydrogen. 6. Glutamic acid derivative according to claim 5 of the general formula 5 '.' 1? I, k i e stmp a m o r i a 7. at. om ky or sulfur, W 3 Ir U P i nu - (CH 2) CH = CH-, - (CH ₂ ) ₃ -, - (CH ₂ ) d -, - (CH 2) 6 an Iry atom; ·>. l k u or ~ (CH ₂ ) 0 ' bi i, p n 0 s 1. m i J, 0 and 3 '; zol - 1 y 1 night O i. ”i -y .ltjVnu don't hit ', 2, 4-i, r. Azo.) (i) El L · » with , m 0, p 0 a R ¹ Group ·,! ..! phenyl, 2 - met; was phenyl In HU 1 4- met by i for tyl O ^v ou, 4-hydroxy-phenylenes. 4- Even at 11 or ι..ι 4 - CY J | -_> cr * p s f or the first iv I. AH · t .ι 4 - ^f 1, ι, 4.4 - L, E t. m. n. tert-butyl, 4-acetylphenyl, 4-trifluoromethylphenyl, 41 h. or phenylovriu. 2-bromophenyl, iodophenyl 8-1 ^verifies Ly.1 naphthylsulfonyl, 2-riaf tulle, 6-bromonaphth-2-yl, 1, 6-bromriaft -? - yiovou, 3,4-methylenedioxyphenyl verifies even ridarr5 -ymbol. 1,2,3,4-tetramethyldronaphthyl, 1,1,4,4-tetramethyl-1,2,3,4-tetramhydrofluoride, fluoro err 2 - in I. o ', ou, di benzofuran an ^- <- - y 1 o vou, 5,6,78 - t. et r ahy di od i bei s> rf ur ar i-2-y 1 o vou, 2-moth y-Ibenzofuran-5-y-left, 5'-azidyl, 5-yl, pyrimidin-2-yl or 1-methyl-tetrazin-5-yl or III-yl; ) n ', o m, m 0 or 1, P * or 2 and R ^{1 of a} group of 1, 2, 4-thiazolyl and each R ² independently of one another 2 - p i i rl y j o v i i t o o pheny l · iv »> u. 2 - f. · H tor f or thi i. T, 4 - ph i r pheny l and 4- (i j t.rof eiay Jj.> Vi iij, r a R * and R ⁴ always atr iim vnbíktj. 7. Der i v,. · I glu t.am _(jl vé Kyse 11 riy pod.1 e riárriki.t ( , -yi> 6rib ^! í ni ^ hr v ;; o if f i · ) which has 25.4? · i , or 25.55 knnfl.gura, -i. 8. Der i 91uternově The acid of claim ¹ i ifrf-.Tj'i1) r.i vro ¹ · 1, ktt. · (Yeah yeah 3- (4- (6-Phenylhexyl) phenoxy) glycerol; y) giu t and mi; your k y sel .i r ia, 3- (2-naphthalaloxy) phenoxy) glutamic acid, 3- (6-bromo-2-naphthyloxy) g. 8 - (4- (2- (4-nitro) -ethyl) ether) phenoxy) glutamic acid 3- (2-Fluorenoxy) glutamic acid, 3- (2-dibenzofuranoxy) glutamic acid a 3- <5,6,7, S-tetrahydro-2-dibenzofuranoxy) glutamic acid, C2S, 43) -3- (6-bromo-2-naphthyloxy) glutamic acid and (25,43) -3- (4-C6-phenylhexyl) phenoxy) glutamic acid. Use of a glutamic acid derivative of the formula I according to claim 1 for the preparation of a pharmaceutical composition for the treatment of conditions requiring modulation of neurotransmission of the excitatory amino acid recipe. 10. A pharmaceutical composition for the treatment of conditions requiring modulation of neurotransmission of an excitatory amino acid recipe which comprises as an active ingredient a glutamic acid derivative of the formula I as claimed in claim 1 together with one or more agents selected from the group consisting of a pharmaceutically acceptable carrier. , diluent or excipient. A process for the preparation of a glutamic acid derivative of the formula I as claimed in claim 1 to 8, characterized in that a compound of the general formula XIX (XIX) is hydrolyzed, wherein R® represents a hydrogen atom or a carboxyl protecting group. 8, or a salt thereof. 12. Compound of Formula XIX XIX where means Z group NR ⁵ . an oxygen atom or a sulfur atom, In the group -CH <3-p>, -CCH2jq-, -CCH3) qCH <3-p>, -CCH2) qCO-, -CCH 3 _q CH = CHCCH 2) q -, -CCH 3 q q = CH-. -CH = CHCO-. -CH = CHCOR ⁶ , -CCHa, CHCHR ⁶ , - (CHa) _q CHOH. -CCIfejqCOR ⁶ , -CKClfejq-, ^NR5, Sat. SO2 oxygen or sulfur atom, n O or 1, m 0 or 1, P 0, 1, 2 or 3, q 0 to 6 r 1 or 2 with 0 or 1, provided that the sum of n, m, pass is at least 1, R ¹ and R ² independently of each other an aryl group, a substituted aryl group, a heterocyclic group or a substituted heterocyclic group. R ⁶ is hydrogen. (C 1 -C 10 alkyl, acyl or SO 2 alkyl) C 1 -C 4 alkyl, R ^{6 is a} C 1 -C 10 alkyl group, provided that when n is 0 and s 1, R ¹ is a tetrazolyl, triazolyl group. pyridazinyl. pyrimidinyl. pteridinyl, 1,2,4-triazine-3,5-dionyl, pyrazolonyl, 7H-purinyl, xanthinyl, 3-ethyl-5-hydroxy-1,2,4-thiadiazolyl, 3-hydroxy-1,2,4-thiadiazolyl, rhodaninyl. hydantoinyl and pseudothiohydro-9S dantolnyl, and under the longer condition that when π is 1, m 1 and W is 0 (CH 2) q -, NR 5, SO, SO 2, oxygen or sulfur means s 1 and that in the case where n is 0 and s is 0, then m 1 a W group formula - (CH ₂ ) _q CO-, - (CH ₂ ) _q O, -CK = CHCO-, -CH = CHCOOR 6, - (CH ₂ ) q CHOHR.fi, - (CH ₂ ) q CH OH, - (CH ₂ ) _q CO R f 1, -O (CH ₂ ) _q -, NR 5, SO, SO ₂ oxygen or nitrogen and * R ⁸ represents a hydrogen atom or a carboxyl protecting group or a salt thereof;